DE60314426T2 - TOTAL SYNTHESIS OF MYRIAPORONES - Google Patents

Abstract

Compounds of the general formula (I) or a pharmaceutically acceptable salt, derivative, prodrug or stereoisomer thereof are provided: wherein the substituent groups defined by R are each independently selected from the group consisting of H, SiR'3, SOR', SO2X, C(-O)R', C(-O)OR', C(-O)NR', substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, heteroaryl or aralkyl; the group R' is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aminoalkyl, aryl, aralkyl and heterocyclic groups; and the group R'' is selected from the group consisting of H, OH, OR', OCOR', SH, SR', SOR', SO2R', NO2, NH2, NHR', N(R')2, NHCOR', N(COR')2, NHSO2R', CN, halogen, C(-O)H, C(-O)R', CO2H, CO2R', CH2OR, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkylidene, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and substituted or unsubstituted heteroaromatic; with the proviso that the compound is not compound 1, 3 or 4 of U.S. Pat. No. 5,514,708. The compounds have antitumour activity. A synthetic route is also provided.

Description

The current This invention relates to novel myriaporone analogs and their use for the treatment of cancer. The current one The invention also relates to a total synthesis of myriaporones and their derivatives.

BACKGROUND OF THE INVENTION

Myriaporone represent a new class of aquatic polyketide-derived Compounds isolated from the Bryozoon Myriapora truncata.

It has been discovered that myriaporones possess antitumor activity. The complete structure of these related compounds has been reviewed in KL Rinehart et al., J. Nat. Prod. 1995, 58, 344 and in U.S. Patent No. 5,514,708 displayed. The described myriaporones 3 and 4 are in an equilibrium mixture between the free hydroxyketone and the hemiketal, as shown in the previous figure.

It gave several unsuccessful attempts to synthesize myriaporones, see z. Taylor, R.E .; Ciavarri, J. C .; Hearn, B.R. 'A Divergent Approach the Myriaporones and Tedanolides: Enantioselective Preparation of the Common Intermediate "Tetrahedron Lett. 1998, 39, 9361; Taylor et al., Org. Lett. 2002, 4, 2853, available in Internet from 02 August 2002.

in view of their interesting biological properties are sought an efficient, stereocontrolled total synthesis of myriaporones and related compounds.

SUMMARY OF THE INVENTION

worin die durch R definierten Substituentengruppen jeweils unabhängig voneinander ausgewählt sind aus der Gruppe bestehend aus H, SiR'₃, SOR', SO2R', C(=O)R', C(=O)OR', C(=O)NR', substituiertem oder unsubstituiertem Alkyl, substituiertem oder umsubstituiertem Alkenyl, substituiertem oder unsubstituiertem Alkinyl, Aryl, Heteroaryl oder Aralkyl;
die Gruppe R' ausgewählt ist aus substituiertem oder unsubstituiertem Alkenyl, substituiertem oder unsubstituiertem Alkinyl, Aminoalkyl, Aryl, Aralkyl und heterozyklischen Gruppen; und
die Gruppe R'' ausgewählt aus der Gruppe bestehend aus H, OH, OR', OCOR', SH, SR', SOR', SO₂R', NO₂, NH₂, NHR', N(R')₂, NHCOR', N(COR')₂, NHSO₂R', CN, Halogen, C(=O)H, C(=O)R', CO₂H, CO₂R', CH₂OR, substituiertem oder unsubstituiertem Alkyl, substituiertem oder unsubstituiertem Haloalkyl, substituiertem oder unsubstituiertem Alkenyl, substituiertem oder unsubstituiertem Alkyliden, substituiertem oder unsubstituiertem Alkinyl, substituiertem oder unsubstituiertem Aryl, substituiertem oder unsubstituiertem Aralkyl und substituiertem oder unsubstituiertem Heteroaromaten;
worin die Substituenten ausgewählt sind aus Halogen, Cyano, Hydroxyl, Nitro, Azido, Carboxamido; Alkyl, Alkenyl, Alkinyl, Alkoxy, Aryloxy, Alkylthio, Alkylsulfinyl, Alkylsulfonyl, Aminoalkyl, Aryl und Heterozyklus;
Unter dem Vorbehalt, dass die Verbindung nicht die als MT332 oder MT381 bezeichnete natürliche Verbindung ist.In a first aspect, the present invention is concerned with compounds of general formula I or a pharmaceutically acceptable salt, derivative or stereoisomers thereof,

wherein the substituent groups defined by R are each independently selected from the group consisting of H, SiR ' ₃ , SOR', SO 2 R ', C (= O) R', C (= O) OR ', C (= O) NR ', substituted or unsubstituted alkyl, substituted or transubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, heteroaryl or aralkyl;
the group R 'is selected from substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aminoalkyl, aryl, aralkyl and heterocyclic groups; and
the group R '' is selected from the group consisting of H, OH, OR ', OCOR', SH, SR ', SOR', SO ₂ R ', NO ₂ , NH ₂ , NHR', N (R ') ₂ , NHCOR ', N (COR') ₂ , NHSO ₂ R ', CN, halogen, C (= O) H, C (= O) R', CO ₂ H, CO ₂ R ', CH ₂ OR, substituted or unsubstituted Alkyl, substituted or unsubstituted haloalkyl, substituted or un substituted alkenyl, substituted or unsubstituted alkylidene, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted heteroaromatic;
wherein the substituents are selected from halo, cyano, hydroxyl, nitro, azido, carboxamido; Alkyl, alkenyl, alkynyl, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, aminoalkyl, aryl and heterocycle;
With the proviso that the compound is not the natural compound designated MT332 or MT381.

According to our results, the natural compounds correspond to 3 and 4 US 5,514,708 the compounds 4a and 3a described in the examples below.

wobei die durch R definierten Substituentengruppen wie vorstehend definiert sind.When R "is CH ₂ OH, compounds of formula I may exist as a mixture of the ketone isomer and the hemicetal isomer (5),

wherein the substituent groups defined by R are as defined above.

Especially we prefer that at least one of the substituents is not hydrogen is. We found that these compounds improved cytotoxicity have.

Myriaporone be made of natural Received sources. Another object of the present invention is a Synthetic pathway to produce myriaporones and their derivatives. That's why the goal is the current one Invention the synthesis of the compounds of formula I as above also where those in which all R groups are H are defined and the intermediates used in the synthesis.

According to the present invention includes a method of this invention involves removing a protecting group from a compound of formula 5a wherein at least one Group R is a protecting group containing the corresponding compound Formula 5b, wherein said at least one R is a hydrogen. This synthetic route can be used for new and well-known myriaporones are used.

A other design the current one Invention is a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt, derivative, prodrug or stereoisomer thereof, or an intermediate compound in theirs Synthesis and a pharmaceutically acceptable carrier.

A further execution the current one Invention is the use of the compounds of formula I, or pharmaceutically acceptable salts, derivatives, prodrugs or stereoisomers thereof as a remedy for cancer.

DETAILED DESCRIPTION OF THE INVENTION

The current This invention relates to compounds of formula I as above Are defined.

In these compounds, the substituents are known to be selected in accordance with the following instructions:
Alkyl groups preferably have 1 to 12 carbon atoms. A more preferred class of alkyl groups has 1 to 8 carbon atoms, more preferably 1 to about 6 carbon atoms, and most preferably 1, 2, 3 or 4 carbon atoms. Methyl, ethyl and propyl, also isopropyl, are particularly preferred alkyl groups in the compounds of the present invention. The term alkyl as used herein, unless modified, refers to both cyclic and non-cyclic groups, but cyclic groups include at least three carbons as ring members.

Preferred alkenyl and alkynyl groups in the compounds of the present invention have one or more unsaturated linkages and from 2 to about 12 carbon atoms, more preferably 2 to about 8 carbon atoms, more preferably 2 to about 6 carbon atoms, most preferably 2, 3 or 4 carbon atoms. The terms alkenyl and alkynyl, as used herein, refer to both cyclic and non-cyclic groups, yet straight or branched non-cyclic groups are generally preferred.

alkylidene can be branched or unbranched and preferably have 1 to 12 carbon atoms. A more preferred class of alkylidene groups is 1 to about 8 carbon atoms, more preferably 1 is about 6 carbon atoms, and most preferably 1, 2, 3 or 4 carbon atoms. Methylidene, ethylidene and propylidene, also isopropylidene, are particularly preferred alkylidene groups in the connections of the present Invention.

preferred Alkylsulfinyl groups in the compounds of the present invention shut down such groups containing one or more sulfoxide (SO) groups and 1 to about 12 carbon atoms, more preferably 1 to about 8 Carbon atoms, more preferably 1 to about 6 carbon atoms to have. Alkylsulfinyl groups having 1, 2, 3, or 4 carbon atoms are particularly preferred.

Preferred alkylsulfonyl groups in the compounds of the present invention include those having one or more sulfoxide (SO ₂ ) groups and from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, even more preferably 1 to about 6 carbon atoms. Alkylsulfonyl groups having 1, 2, 3, or 4 carbon atoms are particularly preferred.

preferred Close aminoalkyl groups such groups having one or more primary, secondary and / or tertiary Have amino groups, and 1 is about 12 carbon atoms, more preferred From 1 to about 8 carbon atoms, more preferably 1 is about 6 Carbon atoms, and more preferably 1, 2, 3 or 4 carbon atoms. secondary and tertiary Amino groups are generally more preferred than primary amino units.

suitable close heterocyclic groups heteroaromatic and heterocyclic groups with one. suitable heteroaromatic groups in the compounds of the present invention contain one, two or three heteroatoms selected from N, O, or S atoms and close e.g. Coumarinyl, also 8-coumarinyl, quinolinyl, also 8-quinolinyl, Pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, Oxazolyl, imidazolyl, indolyl, benzofuranyl and benzothiazole with one. Suitable heteroalicyclic groups in the compounds of current Invention contain one, two or three heteroatoms selected from N, O or S and close for example, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, Morpholino and pyrrolindinyl groups.

suitable Aryl groups in the compounds of the present invention include individual and multiple ring joints, also multiple ring joints with isolated and / or fused aryl groups. Typical aryl groups contain 1 to 3 isolated or condensed rings and 6 to about 18 carbon ring atoms. Particularly preferred aryl groups include substituted or unsubstituted phenyl, naphthyl, biphenyl, phenanthryl, and Anthracyl with one.

References herein to substituted groups in the compounds of the present invention refer to the specific groups, typically alkyl or alkenyl, which may be substituted at one or more available positions by one or more suitable groups, e.g. Halogen, such as fluorine, chlorine, bromine and iodine; Cyano, hydroxyl, nitro, azido, carboxamide; Alkyl groups including groups having from 1 to 12 carbon atoms, preferably from 1 to 6 carbon atoms and more preferably from 1 to 3 carbon atoms; Alkenyl and alkynyl groups having groups with one or more unsaturated linkages and 2 to about 12 carbon atoms or 2 to about 6 carbon atoms; Alkoxy groups, including those having one or more oxygen linkages and from 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms; Aryloxy, such as phenoxy; Alkylthio groups, including units having one or more thioether linkages and from 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms; Alkylsulfinyl groups, including those moieties having one or more sulfinyl linkages and having from 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms; Alkylsulfonyl groups, including those having one or more sulfonyl linkages and from 1 to about 12 carbon atoms, preferably 1 to about 6 carbon atoms; Aminoalkyl groups such as groups having one or more N atoms and from 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms; Aryl having 6 or more carbon atoms, especially phenyl; Aralkyl, such as benzyl; heterocyclic groups, heteroalicyclic and heteroaromatic groups included, especially with 5 to 10 ring atoms, of which 1 to 4 are heteroatoms, more preferably heterocyclic groups with five or six ring atoms and 1 or 2 heteroatoms or with 10 ring atoms and 1 to 3 hetero atoms.

preferred Close R groups Alkyl, alkenyl, and alkynyl, one or more to disposal standing positions substituted by one or more suitable groups could be, e.g. Halogen, such as fluorine, chlorine, bromine and iodine, especially ω-chlorine or perfluoro; Aminoalkyl groups, such as groups containing one or more N Atoms and 1 to about 12 carbon atoms, preferably 1 to about 6 carbon atoms; Aryl having 6 or more carbon atoms has, especially phenyl; Aralkyl, such as benzyl; heterocyclic groups, including heteroalicyclic and heteroaromatic groups, especially with 5 to 10 ring atoms, of which 1 to 4 heteroatoms are more preferably heterocyclic groups having 5 or 6 ring atoms and 1 or 2 heteroatoms or with 10 ring atoms and 1 to 3 heteroatoms, wherein the heterocyclic groups optionally with one or a plurality of substituents, especially amino, such as Dimethylamino, or with keto.

Of the Term "pharmaceutical usable salts, derivatives, prodrugs "refers to a pharmaceutical usable salt, ester, solvate, hydrate or other compound, which provides a compound to the patient after administration (directly or indirectly) as described here. It goes without saying non-pharmaceutically acceptable salts are also included of the invention, since they are used in the preparation of the pharmaceutical useful salts useful could be. The preparation of salts, prodrugs and derivatives can be carried out by in Technique known methods are performed.

pharmaceutical usable salts of compounds as prepared herein for example, from the parent compound, which is a basic or acidic Unit carries, produced by conventional chemical processes. Such salts For example, they are generally prepared by using these compounds in the form of the free acid or base with a stoichiometric Amount of suitable base or acid in water or an organic solvent or a mixture the two be reacted. Generally will not aqueous Media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile prefers. examples for Acid addition salts, which are added, close Acid addition salts of mineral acids, such as hydrochloric acid, Hydrogen bromide, hydrogen iodide, sulphate, nitrate, phosphate and organic Addition salts, such as acetate, malest, fumarate, citrate, Oxalate, succinate, tartrate, Malst, mandelate, methanesulfonate and p-toluenesulfonate with a. examples for alkaline addition salts include inorganic salts, such as for example, sodium, potassium, calcium and ammonium salts, and organic alkaline salts, such as ethylenediamine, ethanolamine, N, N-dialkylenethanolamine, Triethanolamine and basic salts of amino acids.

The Compounds of the invention can in crystalline form both as free compounds or as solvates (e.g., hydrates), and both forms are within the scope of current Invention included. Solvation procedures are general known in the art.

A Compound which is a prodrug of a compound of formula I is included in the scope and spirit of the invention. The term "prodrug" will be in its widest Sense and includes the derivatives in vivo in the compounds of the invention. Experts are easy on such Derivatives, and these close for example, compounds in which a free hydroxy group is converted into an ester derivative.

The Connections of the current ones Invention represented by the formula I described above can, can depending on their asymmetry include enantiomers or diastereomers. The individual isomers and mixtures are within the scope of the present invention.

In a form is the present one Invention extended to compounds of formula I, which differs from the known myriaporones with respect to one or more stereochemical Differentiate positions. Therefore, in this form are the compounds Isomers and derivative of isomers.

Wenn R'' CH₂OH ist, ist die bevorzugte Stereochemie der Verbindungen der Formel 5:

The preferred stereochemistry of the compounds of formula I is as follows:

When R "is CH ₂ OH, the preferred stereochemistry of the compounds of formula 5 is:

Particularly preferred compounds have the following stereochemistry:

We have found out that these particular groups of compounds have improved biological properties.

In another preferred embodiment the current one Invention R '' is a substituted or unsubstituted alkylidene.

In a preferred embodiment of the compounds of the formula 5, at least one of the substituents RC (= O) R '. Particularly preferred is the compound of formula 47:

In another version the compound of the formula I or the formula 5 is at least one of R substituents no hydrogen. Conveniently, each group is which is not hydrogen, a protecting group that is the same or different from each other can be different.

wobei R¹, R², R⁶ und R⁷ Schutzgruppen für Hydroxy sind.Compounds of the following formulas are preferred:

wherein R ¹ , R ² , R ⁶ and R ^{7 are} protective groups for hydroxy.

wobei R¹, R², R⁶ und R⁷ Schutzgruppen für Hydroxy sind;
und von Formel 30:

wobei R¹, R², R⁶ und R⁷ Schutzgruppen für Hydroxy sind.Particular preference is given to compounds of the formula 19:

wherein R ¹ , R ² , R ⁶ and R ⁷ are hydroxy protecting groups;
and of Formula 30:

wherein R ¹ , R ² , R ⁶ and R ^{7 are} protective groups for hydroxy.

Conveniently, R ¹ , R ² , R ⁶ and R ^{7 are} the same protecting groups. These can be selected from TBS (tBuMe ₂ Si), TBDPS (tBuPh ₂ Si), TES (Et ₃ Si), MOM (CH ₃ OCH ₂ -) MEM (CH ₃ OCH ₂ CH ₂ OCH ₂ -), SEM ((CH ₃ ) ₃ SiCH ₂ CH ₂ OCH ₂ -) and Ac- (CH ₃ CO-). Particularly preferred is TBS (tBuMe ₂ Si) or TBDPS (tBuPh ₂ Si).

wobei R¹ eine Schutzgruppe für Hydroxy ist.Compounds of the following formulas are also preferred:

wherein R ^{1 is} a protecting group for hydroxy.

Particular preference is given to compounds of the formulas 20 and 31:

In the above compounds, R ^{1 is} suitably TBS (tBuMe ₂ Si).

das als ein Gemisch aus dem Ketonisomer und dem Hemiketalisomer vorliegen kann, oder in einer der beiden isomeren Formen, worin die durch R definierten Substituentengruppen jeweils unabhängig ausgewählt werden aus der Gruppe bestehend aus H, SiR'₃, SOR', SO₂R' C(=O)R', C(=O)OR', C(=O)NR', substituiertem oder unsubstituiertem Alkyl, substituiertem oder unsubstituiertem Alkenyl, substituiertem oder unsubstituiertem Alkinyl, Aryl, Heteroaryl oder Aralkyl, und worin wenigstens eine Gruppe R ein Wasserstoff ist;
und worin die Gruppe R' ausgewählt ist aus substituiertem oder unsubstituiertem Alkyl, substituiertem oder unsubstituiertem Alkenyl, substituiertem oder unsubstituiertem Alkinyl, Aminoalkyl, Aryl, Aralkyl und heterozyklischen Gruppen;
das die Entfernung einer Schutzgruppe aus einer Zwischenverbindung der Formel

umfasst, worin die durch R definierten Substituentengruppen jeweils unabhängig voneinander ausgewählt sind aus der Gruppe bestehend aus H, SiR'₃, SOR', SO₂R'C(=O)R', C(=O)OR', C(=O)NR', substituiertem oder unsubstituiertem Alkyl, substituiertem oder unsubstituiertem Alkenyl, substituiertem oder unsubstituiertem Alkinyl, Aryl, Heteroaryl oder Aralkyl, und worin das R oder jede R Gruppe, die in Verbindung 5 ein Wasserstoff wird, in der Zwischenverbindung eine Schutzgruppe ist; und worin die Gruppe R' wie definiert ist.The present invention also provides a process for the synthesis of a myriaporone of formula 5,

which may be present as a mixture of the ketone isomer and the hemicetal isomer, or in one of the two isomeric forms wherein the substituent groups defined by R are each independently selected from the group consisting of H, SiR ' ₃ , SOR', SO ₂ R 'C (= O) R ', C (= O) OR', C (= O) NR ', substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, heteroaryl or aralkyl, and wherein at least one group R is a hydrogen;
and wherein the group R 'is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aminoalkyl, aryl, aralkyl and heterocyclic groups;
the removal of a protecting group from an intermediate of the formula

wherein the substituent groups defined by R are each independently selected from the group consisting of H, SiR ' ₃ , SOR', SO ₂ R'C (= O) R ', C (= O) OR', C (= O) NR ', substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, heteroaryl or aralkyl, and wherein the R or each R group which becomes hydrogen in compound 5 is a protecting group in the intermediate compound; and wherein the group R 'is as defined.

Conveniently, more than one group R in the intermediate is a protecting group.

wobei R¹, R², R⁶ und R⁷ Schutzgruppen für Hydroxy sind.A method of this invention may comprise removing at least one protecting group from a compound of Formula 19:

wherein R ¹ , R ² , R ⁶ and R ^{7 are} protective groups for hydroxy.

wobei R¹, R², R⁶ und R⁷ Schutzgruppen für Hydroxy sind.A similar method of this invention may include removing at least one protecting group from a compound of Formula 30:

wherein R ¹ , R ² , R ⁶ and R ^{7 are} protective groups for hydroxy.

Conveniently, R ¹ , R ² , R ⁶ and R ^{7 are} the same protecting group and are removed.

wobei R¹ eine Schutzgruppe für Hydroxy ist.Another method of this invention involves removing a protecting group from a compound of Formula 20:

wherein R ^{1 is} a protecting group for hydroxy.

wobei R¹ eine Schutzgruppe für Hydroxy ist.A similar process involves the removal of a protecting group from a compound of Formula 31:

wherein R ^{1 is} a protecting group for hydroxy.

worin die Substituentengruppen R und R'' wie vorstehend für Formel I definiert sind; was die Derivatisierung einer Verbindung der Formel 5 umfasst,

die als eine Mischung des Ketonisomers und des Hemiketalisomers, oder in einer der beiden isomeren Form vorliegen kann; und worin die Substituentengruppen definiert sind wie in Patentanspruch 25.The invention further provides a process for the synthesis of a myriaporone compound of the formula I:

wherein the substituent groups R and R "are as defined above for formula I; which comprises the derivatization of a compound of formula 5,

which may be present as a mixture of the ketone isomer and the hemicetal isomer, or in one of the two isomeric forms; and wherein the substituent groups are defined as in claim 25.

wobei R¹, R² und R⁴ Schutzgruppen für Hydroxy sind, und L eine stereospezifische Abgangsgruppe ist, die Chiralität einführt.The invention further provides compounds of the following formula

wherein R ¹ , R ² and R ^{4 are} protecting groups for hydroxy, and L is a stereospecific leaving group introducing chirality.

Preference is given to compounds of the formulas 10 and 22:

worin
R¹, R², R⁴ und R⁶ Schutzgruppen für Hydroxy sind;
R⁵ ausgewählt ist aus der Gruppe bestehend aus H, SOR', SO₂R', R', OR', N(R'), N(Me)(MeO), substituiertem oder unsubstituiertem Alkyl, substituiertem oder unsubstituiertem Alkenyl, substituiertem oder unsubstituiertem Alkinyl, Aryl, Heteroaryl oder Aralkyl; und R' die gleiche Bedeutung hat, wie in Anspruch 1 definiert.The invention also provides compounds of the following formula:

wherein
R ¹ , R ² , R ⁴ and R ^{6 are} protective groups for hydroxy;
R ^{5 is} selected from the group consisting of H, SOR ', SO ₂ R', R ', OR', N (R '), N (Me) (MeO), substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, heteroaryl or aralkyl; and R 'has the same meaning as defined in claim 1.

Preference is given to compounds of the formulas 14 and 26:

The The invention also provides a method of making a compound the formula 14, the chain extension a compound of formula 13, a process for the preparation a compound of formula 26, which is the chain extension a compound of formula 25; a method of preparation a compound of formula 19, which is the chain extension a compound of formula 18; and a method of preparation a compound of formula 30, which is the chain extension a compound of formula 29.

worin R1, R2 und R4 Schutzgruppen für Hydroxy sind.The invention also provides compounds of the following formula:

wherein R1, R2 and R4 are protective groups for hydroxy.

Preference is given to compounds of the formulas 11 and 23:

worin R¹, R² und R⁴ Schutzgruppen für Hydroxy sind.The invention also provides compounds of the following formula:

wherein R ¹ , R ² and R ^{4 are} protective groups for hydroxy.

Compounds of formula 8 are preferred:

The Connections of the current ones Inventions can, as in W.R. Roush et al., Org. Lett. 1999, 1, 95 described, from the intermediate compound 6 or its stereoisomers synthetic getting produced.

One Process for the preparation of compounds of the formula I is described in Scheme 1 is shown.

SCHEMA 1

SCHEMA 1

• – Schutz der Verbindung 6 unter Erhalt der geschützten Verbindung 7. Der Schutz wird ausgeführt mit dem jeweiligen Reagenz der ausgewählten Schutzgruppe (wie TBSCl, TESOTf MOMBr oder tBu₂Si(Otf)₂ unter den Bedingungen gemäß den bekannten Verfahren der organischen Synthese (zum Beispiel: Imidazol, DIPEA oder 2,6-Lutidin in DMF oder CH₂Cl₂), alternative Schutzgruppen sind ebenfalls mit einbezogen,
• – Überführen der endständigen Vinylgruppe an den Kohlenstoffatomen 6 und 7 in eine Aldehydfunktion in Verbindung 8. Diese Überführung wird durch Ozonolyse der Vinylgruppe durchgeführt (zum Beispiel mit O₃ in CH₂Cl₂ bei –78°C) oder durch Bildung des entsprechenden Dihydroxyderivates (zum Beispiel mit NMO, OsO₄ in THF:H₂O) Spaltung des Diols zu dem entsprechenden Aldehyd (zum Beispiel mit NaIO₄ in THF:H₂O),
• – Reaktion mit einem Oxazolidinon 9 ergibt Verbindung 10. Das Oxazolidinon 9 wird in das entsprechende Enolat überführt (zum Beispiel mit BuBOTf und Et₃N in CH₂Cl₂ bei –78°C) und bei niedrigen Temperaturen (–30°C) zu 8 gegeben, worauf man 10 erhält. Andere stereospezifische Abgangsgruppen, die die gewünschte Chiralität einführen, sind ebenfalls in den Rahmen des Erfindungsschutzes mit einbezogen,
• – Reduktion von Verbindung 10 um eine 17-Hydroxymethyl-Seitenkette in Verbindung 11 zu erhalten. Diese Reduktion wird mit dem jeweiligen Reagenz (wie z.B LiBH₄) unter den Bedingungen (zum Beispiel in THF:H₂O oder CH₂Cl₂) gemäß den bekannten Verfahren der organischen Synthese durchgeführt, obwohl auch andere Reduktionsmittel in den Rahmen des Erfindungschutzes mit einbezogen sind.
• – weiterer Schutz an der 17-Hydroxylgruppe ergibt Verbindung 12. Dieser Schutz wird mit dem jeweiligen Reagenz der ausgewählten Schutzgruppe (wie zum Beispiel TBSCl, TESCl, MEMCl oder SMCl) unter den Bedingungen gemäß den bekannten Verfahren der organischen Synthese durchgeführt (zum Beispiel: Imidazol, DIPEA, DMAP oder Et₃N in DMF oder CH₂Cl₂), andere Schutzgruppen sind ebenfalls in die Erfindung mit einbezogen,
• – Überführen der endständigen Vinylgruppe der Kohlenstoffatome 4 und 5 in eine Aldehydfunktion in Verbindung 13. Diese Überführung wird durch Ozonolyse der Vinylgruppe durchgeführt (zum Beispiel O₃, in CH₂Cl₂ bei –78°C) oder durch Bildung der entsprechenden Dihydroxyderivate (zum Beispiel mit NMO, OsO₄ in THF:H₂O) und Spaltung des Diols zu dem entsprechenden Aldehyd (zum Beispiel mit NaIO4 in THF:H₂O oder Pb(OAc)₄), in Toluol),
• – Kettenverlängerung am Kohlenstoff 5 um Verbindung 14 zu erhalten. In dem gezeigten Beispiel wird das ausgewählte Reagenz (CH₃C(O)N(CH₃)OCH₃) in das entsprechende Enolat ([(CH₃)₃Si]₂NLi in THF bei –78°C) überführt und bei niedrigen Temperaturen (–78°C) zu 13 zugesetzt um 14 zu erhalten; um den gleichen Zweck zu erreichen können auch andere unter Fachleuten bekannte alternative Verfahren zur Kettenverlängerung verwendet werden,
• – weiterer Schutz an der 5-Hydroxygruppe um Verbindung 15 zu erhalten. Dieser Schutz wird mit dem jeweiligen Reagenz der ausgewählten Schutzgruppe (wie zum Beispiel TBSOTf) unter den Bedingungen (2,6-Lutidin in CH₂Cl₂) gemäß bekannter Verfahren durchgeführt. Es können auch alternative Schutzgruppen verwendet werden,
• – Oxidation der Hydroxygruppe am Kohlenstoff 7 um Verbindung 16 zu erhalten. Diese Oxidation wird mit dem entsprechenden Reagenz (wie zum Beispiel Dess-Martin Periodinan) gemäß den bekannten Verfahren der organischen Synthese (zum Beispiel in CH₂Cl₂) durchgeführt,
• – Entfernung der Schutzgruppe an der Hydroxygruppe in Position 13 ergibt die endständig nicht geschützte Verbindung 17. Das Entfernen der Schutzgruppe wird mit dem jeweiligen Reagenz (zum Beispiel DDQ) der ausgewählten Schutzgruppe (zum Beispiel PMB) unter den Bedingungen gemäß den bekannten Verfahren (zum Beispiel in CH₂Cl₂:H₂O) durchgefürt,
• – Bildung einer endständigen Olefingruppe durch Kettenverlängerung mit Kohlenstoff 14 und 15 ergibt Verbindung 18. Diese Umwandlung wird in zwei Schritten vorgenommen: a) Oxidation der primären Hydroxylgruppe zum entsprechenden Aldehyd mit dem jeweiligen Reagenz (zum Beispiel Dess-Martin Periodinan) und b) Bildung der cis-Doppelbindung über eine Wittig oder Homer Wadsworth-Emmons-Reaktion unter Standardbedingungen; um den gleichen Zweck zu erreichen können auch andere unter Fachleuten bekannte alternative Verfahren zur Kettenverlängerung verwendet werden,
• – Bildung des Keto-Substituenten in Position 7 der Verbindung 19, falls nicht schon vorhanden. Diese Oxidation wird mit dem entsprechenden Reagenz (wie zum Beispiel Dess-Martin Periodinan) unter den Bedingungen gemäß den bekannten Verfahren der organischen Synthese (zum Beispiel in CH₂Cl₂) durchgeführt.
• – Kettenverlängerung mit den Kohlenstoffatomen 1 und 2, wenn sie in Verbindung 19 nicht schon vorhanden sind. Diese Kettenverlängerung wird mit dem entsprechenden Reagenz (wie zum Beispiel BrMgEt) unter den Bedingungen gemäß den bekannten Verfahren der organischen Synthese durchgeführt (zum Beispiel in THF),
• – teilweise oder vollständige Entfernung der Schutzgruppen unter Erhalt der Verbindung 20 oder 4/3. Das Entfernen der Schutzgruppe wird mit dem jeweiligen Reagenz (zum Beispiel TRAF und AcOH) für die ausgewählte Schutzgruppe (zum Beispiel TBS) unter den Bedingungen gemäß den bekannten Verfahren (zum Beispiel in CH₂Cl₂) durchgeführt,
• – und gegebenenfalls Derivatisierung zu einem als Verbindung (I) gezeigten Derivat, worin wenigstens ein R kein Wasserstoff ist, zum Beispiel durch Reaktion mit A_C2O, einem Alkylsäurechlorid oder Anhydrid in Gegenwart der entsprechenden Base (zum Beispiel Et₃N) in einem geeigneten Lösungsmittel, wie zum Beispiel CHCl₃.

For discussion of this scheme, the numbering of the carbon atoms in each molecule refers to the position number in the final product of Formula I, using the numbering indicated for the known compound 3/4. Scheme 1 includes:

• Protection of compound 6 to give protected compound 7. Protection is carried out with the particular reagent of the selected protecting group (such as TBSCl, TESOTf MOMBr or tBu ₂ Si (Otf) ₂ under the conditions according to the known methods of organic synthesis (for example : Imidazole, DIPEA or 2,6-lutidine in DMF or CH ₂ Cl ₂ ), alternative protecting groups are also included,
• Conversion of the terminal vinyl group on the carbon atoms 6 and 7 into an aldehyde function in compound 8. This conversion is carried out by ozonolysis of the vinyl group (for example with O ₃ in CH ₂ Cl ₂ at -78 ° C.) or by formation of the corresponding dihydroxy derivative ( for example with NMO, OsO ₄ in THF: H ₂ O) cleavage of the diol to the corresponding aldehyde (for example with NaIO ₄ in THF: H ₂ O),
• Reaction with an oxazolidinone 9 gives compound 10. The oxazolidinone 9 is converted to the corresponding enolate (for example with BuBOTf and Et ₃ N in CH ₂ Cl ₂ at -78 ° C) and at low temperatures (-30 ° C) 8 given, after which you get 10. Other stereospecific leaving groups that introduce the desired chirality are also included in the scope of the invention protection,
• Reduction of compound 10 to obtain a 17-hydroxymethyl side chain in compound 11. This reduction is carried out with the respective reagent (such as LiBH ₄ ) under the conditions (for example in THF: H ₂ O or CH ₂ Cl ₂ ) according to the known methods of organic synthesis, although other reducing agents are included within the scope of the invention are involved.
• Further protection on the 17-hydroxyl group gives compound 12. This protection is combined with the particular reagent of the selected protecting group (such as TBSCl, TESCl, MEMCl or SMCl) among the Conditions carried out according to the known methods of organic synthesis (for example: imidazole, DIPEA, DMAP or Et ₃ N in DMF or CH ₂ Cl ₂ ), other protective groups are also included in the invention,
• - Conversion of the terminal vinyl group of carbon atoms 4 and 5 in an aldehyde function in compound 13. This conversion is carried out by ozonolysis of the vinyl group (for example, O ₃ , in CH ₂ Cl ₂ at -78 ° C) or by formation of the corresponding dihydroxy derivatives (zum Example with NMO, OsO ₄ in THF: H ₂ O) and cleavage of the diol to the corresponding aldehyde (for example with NaIO4 in THF: H ₂ O or Pb (OAc) ₄ ), in toluene),
• Chain extension on carbon 5 to obtain compound 14. In the example shown, the selected reagent (CH ₃ C (O) N (CH ₃ ) OCH ₃ ) is converted to the corresponding enolate ([(CH ₃ ) ₃ Si] ₂ NLi in THF at -78 ° C) and at low Temperatures (-78 ° C) added to 13 to get 14; to achieve the same purpose, other alternative chain extension techniques known to those skilled in the art may also be used.
• - further protection at the 5-hydroxy group to obtain compound 15. This protection is carried out with the particular reagent of the selected protecting group (such as TBSOTf) under the conditions (2,6-lutidine in CH ₂ Cl ₂ ) according to known procedures. Alternative protecting groups can also be used
• - Oxidation of the hydroxy group on the carbon 7 to obtain compound 16. This oxidation is carried out with the appropriate reagent (such as Dess-Martin Periodinan) according to the known methods of organic synthesis (for example in CH ₂ Cl ₂ ),
• Removal of the protecting group on the hydroxy group in position 13 gives the terminally unprotected compound 17. Deprotection is carried out with the respective reagent (for example DDQ) of the selected protecting group (for example PMB) under the conditions according to the known methods (for example in CH ₂ Cl ₂ : H ₂ O),
• - Formation of a terminal olefin group by chain extension with carbon 14 and 15 gives compound 18. This conversion is carried out in two steps: a) oxidation of the primary hydroxyl group to the corresponding aldehyde with the respective reagent (for example Dess-Martin Periodinan) and b) formation of the cis double bond via a Wittig or Homer Wadsworth-Emmons reaction under standard conditions; to achieve the same purpose, other alternative chain extension techniques known to those skilled in the art may also be used.
• - Formation of the keto substituent in position 7 of the compound 19, if not already present. This oxidation is carried out with the appropriate reagent (such as Dess-Martin Periodinan) under the conditions according to the known methods of organic synthesis (for example in CH ₂ Cl ₂ ).
• - Chain extension with the carbon atoms 1 and 2, if they are not already present in compound 19. This chain extension is carried out with the appropriate reagent (for example BrMgEt) under the conditions according to the known methods of organic synthesis (for example in THF),
• Partial or complete removal of the protecting groups to give compound 20 or 4/3. The removal of the protecting group is carried out with the respective reagent (for example TRAF and AcOH) for the selected protective group (for example TBS) under the conditions according to the known methods (for example in CH ₂ Cl ₂ ),
• - and, optionally, derivatization to give a as the compound (I) shown derivative wherein one R is not hydrogen, at least, for example by reaction with A _C2 O, an alkyl acid chloride or anhydride in the presence of the appropriate base (for example Et ₃ N) in a suitable Solvent, such as CHCl ₃ .

In addition will be different synthetic myriaporonisomers from the intermediate 8 using a different stereospecific leaving group prepared, for example, by using (S) -oxazolidinone instead of (R) -oxazolidinone. The synthetic route for these compounds is shown in Scheme 2 shown.

SCHEMA 2

SCHEMA 2

The Scheme 2 concludes the same reactions as those in Scheme 1, with a different one Stereochemistry in Oxazolidinone 9.

One The aim of the invention is the first total synthesis of myriaporones 3 and 4 and from these compounds or intermediate intermediates to obtain other compounds of the formula I. The synthesis makes it prefers possible the largest possible amount to obtain Myriaporone 3 and 4 by simple means and ways. The synthesis allows also the preparation of the largest possible Number of specific derivatives of myriaporones 3 and 4. In addition, the Synthesis preferably stereoselective, so that four stereoisomers of Myriaporone 3 and 4 can be obtained in pure form. One Another object of this invention is one type of interconnect in the total synthesis, the synthesis is so variable as possible designed to enable the preparation of a large number of derivatives.

In the previous reaction schemes, the hydroxy-protecting groups R ¹ , R ² , R ⁴ , R ⁶ , and R ^{7 can be} any of those described in Protective Groups in Organic Synthesis, TW Greene, PG Wuts, Ed. Wiley Interscience, 3rd Edition may be displayed examples of hydroxy-protecting groups. Examples of hydroxy-protecting groups are given in the following list: Protection for OH group abbreviation ether methyl methoxymethyl MOM benzyloxymethyl BOM methoxyethoxymethyl MEM 2- (trimethylsilyl) ethoxymethyl SEM methylthiomethyl MTM phenylthiomethyl PTM azidomethyl cyanomethyl 2,2-dichloro-1,1-difluoroethyl 2-chloroethyl 2-bromoethyl tetrahydropyranyl THP 1-ethoxyethyl EE phenacyl 4-bromophenacyl cyclopropylmethyl allyl propargyl isopropyl cyclohexyl t-butyl benzyl 2,6-dimethyl benzyl 4-methoxybenzyl MPM or PMB o-nitrobenzyl 2.6-dichlorobenzyl 3,4-dichlorobenzyl 4- (dimethylamino) carbonylbenzyl 4-methylsulfinylbenzyl MSIB 9-anthrylmethyl 4-picolyl Protection for OH group abbreviation Heptafluoro-p-tolyl Tetrafluoro-4-pyridyl Trimethylsilyl TMS t-butyldimethylsilyl TBDMS t-butyldiphenylsilyl TBDPS triisopropylsilyl TIPS ester Arylformat Arylacetat Aryllevulinat Arylpivaloat ArOPv aryl benzoate Aryl-9-fluorocarboxylate Arylmethylkarbonat 1-Adamantylkarbonat t-Butylkarbonat BOC-OAr 4-Methylsulfinylbenzylkarbonat Msz-Oar 2,4-dimethylpent-3-ylkarbonat Doc-Oar Aryl-2,2,2-trichlorethylkarbonat Arylvinylkarbonat Mylbenzylkarbonat Arylkarbamat dimethylphosphinyl Dmp-OAr dimethylphosphinothioyl Mpt-OAr diphenylphosphinothioyl DPT Oar Arylmethansulfonat Aryltoluolsulfonat Aryl-2-formylbenzenesulfonate

Preferred R ² , R ⁴ , R ⁶ and R ⁷ are TBS (tBuMe ₂ Si), TBDPS (tBuPh ₂ Si), TES (Et ₃ Si), MOM (CH ₃ OCH ₂ -), MEM (CH ₃ OCH ₂ CH ₂ OCH ₂ -), SEM ((CH ₃ ) ₃ SiCH ₂ CH ₂ OCH ₂ -) and Ac-, and more preferred are TBS and TBDPS. It is also preferred that R ² , R ⁴ , R ⁶ and R ^{7 are} the same protecting group. Preferably, R ^{1 is} PMB (p-MeO-Ph-CH ₂ -). The reactions for introducing and removing the protective group shown in the above reaction schemes are carried out according to the prior art.

Scheme R ³ is selected from the group consisting of H, OH, = O, OR ', OSiR', OSOR ', OSO ₂ R', OCOR ', OCOOR', CONR ', NHR' and NR 'R'. R 'has the same meaning as defined in formula I. Preferably, R ^{3 is} hydroxy or = O.

The group listed as R ⁵ in the schemes is selected from the group consisting of H, SOR ', SO ₂ R', C (= O) R ', C (= O) OR', C (= O) NR ' , substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, heteroaryl or aralkyl. And R 'has the same meaning as defined in Formula I. Preferably, R ^{5 is} C 1 -C 6, and more preferably, it is ethyl.

The identity the connections 9 and 21 can be changed according to the state the technique with other ways of compound 8 the compounds 11 and 23 to receive.

The relative stereochemistry at C-8-C-12 of compounds 3 and 4 based on a comparison of the coupling constants cited therein as the same as in Patent No. 5,514,708, 1996. It was also the stereochemistry of the starting material 6 described above already by W.R. Roush et al., Org. Lett. 1999, 1, 95.

Around to confirm this information, was the stereochemistry of these carbon based on NOESY and COZY investigations of the intramolecular epoxide on the open product 33, which was prepared from 11a in two steps (Scheme 3).

SCHEMA 3

SCHEMA 3

The Absolute configuration at C-8 to C-12 was easily done using NOE experiments determined. On the basis of the coupling constant (J = 1.5 Hz), a relative syn stereochemistry was derived at C-11-C12. An NOE signal between H-11 and H-14 shows that both are in axial position.

A relative anti-stereochemistry at C-6-C-7 was from the small Derived the value of the coupling constants of the acetonide 34, which derived from compound 11a (Scheme 4).

SCHEMA 4

SCHEME 4

Finally became the stereochemistry of compounds 3a, 3b, 4a and 4b at C-5 by conversion of the 1,3-diols of 15a and 15b in the corresponding 1,3-syn and anti-acetonides assigned. Scheme 5).

SCHEMA 5

SCHEMA 5

The stereochemistry of the syn- and anti-1,3-diol acetonides was assigned according to SD Rychnovsky et al., J. Org. Chem. 1993, 58, 3511-3515, from the ¹³ C shifts of the acetal-methyl groups. In general, the syn-1-diol acetonides have acetalic methyl shifts at 19 and 30 ppm, respectively, while the anti-acetonides both have methyl shifts at approximately 25 ppm. In fact, we tested the reliability of this method because the ¹³ C NMR spectrum of the syn acetonide 35b has an axial methyl group at about 20.2 ppm and an equatorial methyl group at about 30.0 ppm, whereas the ¹³ C spectrum of the anti Acetonide 35a has both methyl groups at 24.4 and 25.2 ppm.

Unfortunately, the stereochemistry of 3c, 3d, 4c, and 4d could not be determined by preparing the acetonides of 26a and 26b, as these compounds could not be separated by conventional methods. In these cases, the configuration at the C-5 position was proved by transfer of 11a to the 1,3-diols 38a and 38b, which can be easily separated. After several reactions, these led Compounds, for example, to the known interconnect 27c and 27d. The stereochemistry of these compounds was determined from the ¹³ C chemical shifts of the corresponding acetonides 36a (= 24.1, 25.0 ppm) and 36b (= 19.7, 29.9 ppm) (Scheme 6).

SCHEMA 6

SCHEMA 6

The relative stereochemistry for H-5 and H-6 of myriaporones 3 and 4 were analyzed by coupling constants between the protons of the six-membered rings in the hemiketal simply protected Myriaporones 20 and 31 (Scheme 7) closed.

For 20a and 31b, H-4 became δ 1.73 and 1.58 ppm, each with coupling constants of 14.5, 3.5 Hz as determined axially. The other H-4s with high-field shifts at δ 2.02 and 2.03 ppm for each compound has coupling constants of 14.0, 3.5, respectively Hz and 14.5, 3.5 Hz. These values indicate that the proton H-5 is equatorial must be arranged.

Corresponding The coupling constants between H-5 and H-6 are included in both cases approximately 2 Hz, which is an equatorial Arrangement of H-5 indicates. It is concluded that the relative Stereochemistry for H-5 and H-6 is syn.

On the other hand, the ¹ H-NMR spectra of the compounds 20b and 31a are different from those of the compounds 20a and 31b in terms of coupling contant and, above all, chemical shift. For these compounds, the coupling constants between H-4 (ax) and H-5 are approximately 12, 13 Hz, indicating an axial position for H-5.

In addition are the coupling constants between H-5 and H-6 in accordance with the fact that H-6 is in axial position around the interaction low to hold, and consequently, to a relative anti-stereochemistry for H-5 and H-6 closed.

SCHEMA 7

SCHEME 7

The Stereochemistry at C-3 in the hemiketal compounds failed NOE experiments are determined. In Scheme 7 is the hemiketal group at C3 arbitrarily set as equatorial.

A another particularly preferred embodiment the current one Invention are pharmaceutical compositions used as antitumor agents useful are, as an active ingredient, a compound or compounds contains the invention as well as the procedures for their preparation.

One important feature of the above-described compounds of Formula I is their bioactivity and especially their cytotoxic activity. Deliver with this invention we new compounds pharmaceutical compounds general formula I, which have cytotoxic activity, and their use as an antitumor agent. Thus, the present invention continues to provide pharmaceutical Composition with a compound of this invention, pharmaceutically usable salts, derivatives, prodrugs or stereoisomers thereof a pharmaceutically acceptable carrier.

Examples pharmaceutical compositions include solids (tablets, Pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) with suitable composition for oral, external acting or parenteral administration.

The Administration of these compounds or compositions of the present invention may by any suitable method, such as intravenous infusion, oral administration, intraperitoneal and intravenous administration. We prefer to use infusion times of up to 24 hours 2-12 hours, more preferably 2-6 hours to prefer. Short infusion times, the treatment without hospitalization overnight allow in hospital are particularly desirable. Nevertheless, if necessary, the infusion may take 12 to 24 hours or go longer. It is suggested to infuse in appropriate To perform intervals of 1 to 4 weeks. Pharmaceutical compositions, The compounds of the invention may contain via liposome or encapsulation be released in nanospheres, in sustained-release formulations or by other standard release agents are released.

The correct dosage of the compounds varies according to the specific formulation, the route of administration and the specific location of the treatment receiver and tumors. Other factors, such as age, body weight, gender, diet, time the administration, rate of excretion, condition of the receiver Drug compositions, sensory responses and seriousness of the disease be considered. The administration can be continuous or periodically with the maximum approved dose.

The Compounds and compositions of this invention can be used with other medicines are used together for a combination therapy to accomplish. The other medicines can be part of the same recipe be delivered, or as a separate recipe, administered at the same time or at a different time.

Antitumor activities of this Close connections including leukemia, Lung cancer, colon carcinoma, kidney cancer, prostate cancer, ovarian cancer, Breast cancer, pancreatic cancer, Cervical carcinoma, Sarcomas and melanomas included.

The current Invention is further clarified by the following examples, however, it is not limited to these. As you can see the method the synthesis of myriaporone compounds with the desired Stereospecificity.

EXAMPLES

Example 1: Compound 7a

To a solution of 6 (3.51 g, 7.8 mmol) in CH ₂ Cl ₂ (40 mL) at 23 ° C was added imidazole (1.59 g, 23.4 mmol) and TBSCl (1.76 g, 11.7 mmol) was added. The reaction mixture was stirred at 23 ° C for 3 h. 0.1 N HCl was added until pH = 4-5 was reached, and the mixture was extracted with CH ₂ Cl ₂ (2x). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 10: 1) to give compound 7a (3.44 g, 78%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.23 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.83 (m, 1H ), 4.99 (dd, J = 10.5, 1.8 Hz, 1H), 4.86 (dd, J = 17.4, 2.1 Hz, 1H), 4.42 (s, 2H) , 3.80 (s, 3H), 3.44 (m, 2H), 3.33 (d, J = 6.6 Hz, 1H), 2.47 (d, J = 9.6 Hz, 1H) , 1.25 (d, J = 6.6 Hz, 3H), 0.91 (s, 9H), 0.88 (s, 9H), 0.13 (s, 3H), 0.04 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H). ¹³ C NMR (75 MHz, CDCl ₃₎ δ 159.1, 136.2, 130.3, 129.1, 117.1, 113.7, 72.9, 72.6, 64.9, 64.6 , 63.9, 55.2, 51.3, 33.1, 25.9, 25.8, 18.2, 18.1, 14.9, 13.3, -4.2, -5.3 , -5,4, -5,5.
MS (ESI) m / z: 587 (M + 23) ⁺ .
[α] ²⁵ _D -9.5 (c 0.52, CH ₂ Cl ₂ ).
R _f = 0.61 (Hex: EtOAc, 4: 1).

Example 2: Compound 7b

Compound 7b was prepared in the same way as 7a from the corresponding precursor of 6 according to the method described by W. Roush et al., Org. Lett. 1999, 1, 95) was prepared as a colorless oil using equivalent amounts of TESOTf instead of TBSOTf for the protection of the secondary alcohol.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.24 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.92 to 5.80 (m, 1H), 5.02 (dd, J = 10.2, 1.8 Hz, 1H), 4.90 (dd, J = 17.4, 1.8 Hz, 1H), 4.42 ( s, 2H), 3.78 (s, 3H), 3.56-3.42 (m, 3H), 3.38-3.34 (m, 2H), 2.52 (d, J = 9, 0 Hz, 1H), 2.27-2.23 (m, 1H), 1.81-1.76 (m, 1H), 1.27 (s, 3H), 1.10 (d, J = 6 , 6Hz, 3H), 0.98 (t, J = 7.8Hz, 9H), 0.90 (s, 9H), 0.71-0.62 (m, 6H), 0.05 (s , 3H), 0.04 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 159.1, 136.4, 130.2, 129.0, 116.8, 113.6, 76.9, 72.8, 72.6, 64.7 , 64.6, 63.8, 55.0, 51.1, 33.2, 25.7, 18.0, 14.8, 13.1, 6.9, 4.8, -5.3, -5.5.
MS (ESI) m / z: 587 (M + 23) ⁺ , 565 (M + 1) ⁺ .
R _f = 0.62 (hexane: EtOAc, 4: 1).

Example 3: Compound 7c

To a solution of 6 (450 mg, 1 mmol) in CH ₂ Cl ₂ (20 mL) was added at 0 ° C DIPEA (1.74 mL, 10 mmol) and MOMBr (0.45 mL, 5 mmol). The reaction mixture was stirred at 0 ° C for 4 h. Then a saturated aqueous solution of NH ₄ Cl was added and the mixture extracted with CH ₂ Cl ₂ (2 x 30 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Hex: EtOAc, 10: 1) to give Compound 7c (250 mg, 51%) as a colorless oil ,
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.24 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 5.90 to 5.78 (m, 1H), 5.04 (dd, J = 10.2, 2.1Hz, 1H), 4.95 (dd, J = 17.4, 2.1Hz, 1H), 4.56 ( s, 2H), 4.43 (s, 2H), 3.80 (s, 3H), 3.51-3.40 (m, 1H), 3.37-3.34 (m, 4H), 3 , 33 (s, 3H), 2.52 (d, J = 9.3 Hz, 1H), 2.43-2.40 (m, 1H), 1.79-1.65 (m, 1H), 1.25 (s, 3H), 1.09 (d, J = 6.6Hz, 3H), 0.91 (s, 9H), 0.14 (s, 3H), 0.04 (s, 3H ).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 159.4, 136.4, 130.6, 129.4, 117.6, 114.0, 96.8, 78.2, 73.1, 72.7 , 69.0, 64.8, 64.7, 55.6, 55.5, 49.2, 33.4, 26.2, 18.5, 15.2, 13.5, -3.9, -5.3.
R _f = 0.52 (Hex: EtOAc, 4: 1).

Example 4: Compound 7d

To a solution of the corresponding diol (581 mg, 1.73 mmol) in CH ₂ Cl ₂ (20 mL) at 0 ° C was added 2,6-lutidine (0.61 g, 5.2 mmol) and t-Bu ₂ Si (OTf) ₂ (9.48 mL, 2.6 mmol) was added. The reaction mixture was stirred at 0 ° C for 2 h. Then a saturated aqueous solution of NH ₄ Cl was added and the mixture extracted with CH ₂ Cl ₂ (2 x 30 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 10: 1) to give Compound 7d (330 mg, 40%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.23 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.40 (ddd, J = 17.1, 9.9, 8.7 Hz, 1H), 5.10 (dd, J = 10.5, 1.8 Hz, 1H), 5.06 (dd, J = 17.1, 1 , 8Hz, 1H), 4.41 (s, 2H), 4.35 (dd, J = 11.1, 3.0Hz, 1H), 4.06 (d, J = 3.0Hz, 1H ), 4.00 (dd, J = 11.1, 2.4 Hz, 1H), 3.80 (s, 3H), 3.34 (d, J = 6.3 Hz, 2H), 2.72 (d, J = 9.3Hz, 1H), 2.41-2.37 (m, 1H), 1.78-1.73 (m, 1H), 1.28 (s, 3H), 1, 09 (d, J = 6.6 Hz, 3H), 1.07 (s, 9H), 1.05 (s, 9H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 159.4, 136.9, 130.7, 129.2, 116.9, 114.0, 79.6, 73.1, 72.8, 70.4 , 63.7, 62.3, 55.5, 47.0, 33.3, 28.6, 27.7, 23.5, 21.0, 15.1.
MS (ESI) m / z: 499 (M + 23) ⁺
R _f = 0.41 (Hex: EtOAc, 4: 1).

Example 5: Compound 8a

Via a solution of 7a (21.94 & 38.7 mmol) in CH ₂ Cl ₂ (150 mL) was passed for 50 min at -78 ° C, an O ₃ stream. Then, Ph ₃ P (30.43 g, 116.1 mmol) was added and the mixture was warmed to room temperature and stirring was continued for 12 h. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 20: 1) to give compound 8a (15.82 g, 72%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 9.67 (d, J = 3.0 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 4.38 (m, 2H), 3.84 (dd, J = 10.2, 5.1 Hz, 1H), 3.80 (s, 3H), 3.69 (m, 2H), 3.41 (dd, J = 9.3, 5.1 Hz, 1H), 3.31 (t, J = 9.0 Hz, 1H), 2.59 (d, J = 9.3 Hz, 1H), 2.50 (m, 1H), 1.81 (m, 1H), 1.30 (s, 3H), 1.06 (d, J = 6.3 Hz, 3H) , 0.86 (s, 18H), 0.14 (s, 3H), 0.04 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 203.8, 159.5, 130.3, 129.4, 114.0, 76.5, 73.2, 73.0, 65.1, 64.0 , 60.1, 57.9, 55.4, 33.6, 26.0, 26.0, 18.3, 15.0, 13.0, -4.0, -5.2, -5, 3, -5.5.
MS (ESI) m / z: 589 (M + 23) ⁺ .
[α] ²⁵ _D -11.6 (c 0.50, CH ₂ Cl ₂ ).
R _f = 0.59 (Hex: EtOAc, 4: 1).

Example 6: Compound 8b

To a solution of 7b (0.86 g, 1.52 mmol) in THF: H ₂ O (10: 1.22 mL) at 23 ° C was added NMO (0.623 g, 5.32 mmol) and OsO ₄ (4 , 56 mL, 0.456 mmol, 0.1 M in ^t BuOH) was added and the reaction mixture was stirred at 23 ° C overnight. Florisil (6 g), NaHSO ₃ (6 g), and EtOAc (100 mL) were added and the mixture stirred vigorously for 30 minutes. The mixture was filtered through Celite and the filtrate concentrated to give the corresponding diol. To a solution of this diol in THF (10 mL) at 0 ° C was added a solution of NaIO ₄ (1.95 g, 9.12 mmol) in H ₂ O (8 mL) and the mixture was stirred at 23 ° C for Stirred for 1 h. The reaction was quenched by addition of a saturated aqueous solution of NH ₄ Cl (20 mL) and then extracted with CH ₂ Cl ₂ (2 x 20 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 10: 1) to give compound 8b (0.67 g, 78%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 9.68 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 4.36 (q, J = 11.4 Hz, 2H), 3.83 (dd, J = 10.2, 5.1 Hz, 1H), 3.76 (s , 3H), 3.74 (d, J = 6.3 Hz, 1H), 3.67 (dd, J = 10.2, 5.7 Hz, 1H), 3.39 (dd, J = 9, 3, 5.1 Hz, 1H), 3.30 (t, J = 9.0 Hz, 1H), 2.60 (d, J = 9.3 Hz, 1H), 2.47-2.40 ( m, 1H), 1.82-1.78 (m, 1H), 1.28 (s, 3H), 1.04 (d, J = 6.6Hz, 3H), 0.92 (t, J = 7.8Hz, 9H), 0.85 (s, 9H), 0.62 (q, J = 7.8Hz, 6H), 0.01 (s, 3H), 0.00 (s, 3H ).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 203.4, 159.1, 129.9, 129.0, 113.6, 75.9, 72.8, 72.6, 64.9, 63.5 , 59.7, 57.4, 55.0, 33.3, 25.6, 17.9, 14.6, 12.5, 6.7, 4.6, -5.5, -5.7 ,
MS (ESI) m / z: 589 (M + 23) ⁺ .
R _f = 0.54 (hexane: EtOAc, 4: 1).

Example 7: Compound 9

Compound 9 was prepared according to the method described in DA Evans et al., J. Am. Chem. Soc. 1984, 106, 4261-4263.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.21 (m, 1H), 7.12 (m, 1H), 4.44 (m, 1H), 4.20 (m, 2H), 2.36 (m, 1H), 1.91 (dd, J = 6.6, 1.2Hz, 3H), 0.88 (d, J = 6.9Hz, 3H), 0.83 (d, J = 6.9 Hz, 3H).

Example 8: Compound 10a

To a solution of 9 (17.75 g, 0.09 mol) in CH ₂ Cl ₂ (270 mL) at -78 ° C was Bu ₂ BOTf (99 mL, 1M in CH ₂ Cl ₂ , 0.099 mmol) and Et ₃ N (17.56 mL, 0.126 mol) was added. The reaction mixture was stirred at -78 ° C for 1 h, cooled at 0 ° C for 15 min and again at -78 ° C. This solution was added in three portions over 5 h at 0 ° C via a solution of 8a (17.18 g, 0.03 mol) in CH ₂ Cl ₂ (100 mL) and the mixture was stirred at -30 ° C for stirred for another 12 h. Then a saturated aqueous solution of NH ₄ Cl (300 mL) was added and the reaction extracted with CH ₂ Cl ₂ (2 x 200 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in 400 mL of ether, 200 mL of buffer solution and 200 mL of H ₂ O ₂ and the mixture was stirred at 0 ° C for 1 h. Then the reaction was extracted and the organic phase washed with a saturated aqueous solution of NaHCO ₃ (200 mL) and brine (200 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hex: EtOAc, from 10: 1 to 2: 1) to give compound 10a (21 g, 92%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.19 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 5.93 (m, 1H ), 5.41 (d, J = 17.1 Hz, 1H), 5.28 (d, J = 9.3 Hz, 1H), 4.92 (t, J = 9.6 Hz, 1H), 4.63 (dddd, J = 9.3, 6.3, 5.1, 1.5 Hz, 1H) 4.43 (s, 3H), 4.34 (m, 1H), 4.12 (m , 2H) 3.85 (m, 1H), 3.80 (s, 3H), 3.73 (m, 2H), 4.44 (m, 2H), 2.58 (d, J = 9.3 Hz, 1H), 2.30 (m, 1H), 1.81 (m, 1H), 1.38 (s, 3H), 1.10 (d, J = 6.6 Hz, 3H, 0.93 (s, 9H), 0.87 (s, 9H), 0.84 (d, J = 7-5Hz, 3H), 0.80 (d, J = 6.9Hz, 3H), 0.17 (s, 3H), 0.12 (s, 3H), 0.09 (s, 3H), 0.04 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 172.0, 159.0, 153.3, 135.3, 129.9, 128.6, 113.7, 77.4, 72.6, 71.0 , 64.0, 63.4, 62.6, 59.8, 58.4, 58.0, 55.2, 51.2, 45.2, 40.1, 33.6, 26.7, 28 , 3, 27,8, 26,1, 25,8, 18,3, 17,9, 15,1, 14,6, 14,3, 13,1, -4,4, -5,4, - 5.5, -5.6.
MS (ESI) m / z: 786 (M + 23) ⁺ .
[α] ²⁵ _D + 3.1 (c 0.53, CH ₂ Cl ₂ ).
R _f = 0.35 (Hex: EtOAc, 4: 1).

Example 9: Compound 10b

The title compound was prepared as described above from 8b (1.2 g, 2.11 mmol). Chromatography (SiO 2,) gave 10b (1.16 g, 80%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.20 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 5.85 to 6.03 (m, 1H), 5.19-5.44 (m, 2H), 4.93 (t, J = 9.3Hz, 1H), 4.59-4.64 (m, 1H), 4, 42-4.46 (m, 1H), 4.42 (s, 2H), 4.19-4.36 (m, 4H), 4.05-4.15 (m, 2H), 3.80 ( s, 3H), 3.65-3.83 (m, 3H), 3.40-3.46 (m, 1H), 2.57 (d, J = 9.3Hz, 1H), 2.27 -2.36 (m, 1H), 1.78-1.56 (m, 1H), 1.56-1.64 (m, 1H), 1.37 (s, 3H), 1.28-1 , 38 (m, 6H), 0.92 (s, 9H), 0.88-0.99 (m, 6H), 0.62-0.68 (m, 9H), 0.09 (s, 3H ), 0.04 (s, 3H).
R _f = 0.42 (Hex: EtOAc, 4: 1).

Example 10: Compound 11a

To a solution of 10a (14.5 g, 18.9 mmol) in THF: H ₂ O (5: 1, 120 mL) at 0 ° C was LiBH ₄ (141.9 mL, 2.0 M in THF, 283.7 mmol) was added. The reaction mixture was stirred at 0 ° C for 30 min and at 23 ° C for 6 h. A saturated aqueous solution of NH ₄ Cl (150 mL) was added and the mixture was extracted with EtOAc (3 x 150 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in 400 mL of ether, 200 mL of buffer solution and 200 mL of H ₂ O ₂ and the mixture was stirred at 0 ° C for 2 h. Then the reaction was extracted and the organic phase washed with a saturated aqueous solution of NaHCO ₃ (2 x 200 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 5: 1) to give compound 11a (10.5 g, 87%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.22 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 5.84 (m, 1H ), 5.21 (d, J = 8.7Hz, 1H), 5.14 (d, J = 17.4Hz, 1H), 4.42 (s, 2H), 4.19 (m, 1H ), 3.84 (m, 1H), 3.80 (s, 3H), 3.75 (m, 1H), 3.61 (m, 2H), 3.48 (m, 2H), 3.36 (m, 2H), 2.53 (d, J = 9.3Hz, 1H), 2.27 (m, 1H), 1.80 (m, 1H), 1.32 (s, 3H), 1 , 05 (d, J = 6.9 Hz, 3H), 0.91 (s, 9H), 0.88 (s, 9H), 0.15 (s, 3H), 0.09 (s, 3H) , 0.05 (s, 3H), 0.04 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 159.5, 137.6, 130.3, 129.4, 118.3, 114.0, 73.2, 73.0, 71.2, 64.9 , 64.4, 60.4, 55.5, 51.1, 47.0, 33.5, 29.9, 26.4, 26.3, 26.0, 18.4, 18.2, 15 , 0, 14.0, -4.2, -5.1, -5.2.
MS (ESI) m / z: 662 (M + 23) ⁺ .
[α] ²⁵ _D + 0.7 (c 0.54, CH ₂ Cl ₂ ).
R _f = 0.2 (Hex: EtOAc, 4: 1).

Example 11: Compound 11b

The title compound was prepared from 10b (1.53 g, 2 mmol) as described above. Chromatography (SiO 2,) gave 11b (1 g, 80%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.22 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.92 to 5.80 (m, 1H), 5.92-5.80 (m, 1H), 5.21 (dd, J = 10.2, 2.1Hz, 1H), 5.14 (dd, J = 17.1 , 2.1Hz, 1H), 4.40 (s, 2H), 4.19-4.16 (m, 1H), 3.84 (dd, J = 6.0, 1.5, 1H), 3.80 (s, 3H), 3.72 (dd, J = 6.3, 2.4Hz, 1H), 3.62 (d, J = 4.5Hz, 1H), 3.56 (i.e. , J = 3.6 Hz, 1H), 3.52-3.48 (m, 1H), 3.38-3.33 (m, 2H), 2.53 (d, J = 9.0 Hz, 1H), 2.27-2.22 (m, 1H), 1.83-1.78 (m, 1H), 1.73-1.67 (m, 1H), 1.30 (s, 3H) , 1.04 (d, J = 6.9 Hz, 3H), 0.95 (t, J = 7.8 Hz, 9H), 0.87 (s, 9H), 0.67 (q, J = 7.8 Hz, 6H), 0.05 (s, 3H), 0.04 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 159.2, 137.4, 130.1, 129.1, 118.0, 113.7, 77.4, 72.9, 72.7, 71.1 , 64.9, 64.3, 64.2, 60.2, 55.2, 51.0, 46.6, 33.3, 25.7, 17.9, 14.8, 13.5, 6 , 8, 4,7, -5,3, -5,5.
R _f = 0.18 (Hex: EtOAc, 4: 1).

Example 12: Compound 12a

To a solution of 11a (7.43 g, 11.6 mmol) in CH ₂ Cl ₂ (100 mL) at 23 ° C was added imidazole (3.16 g, 46.4 mmol) and TBSCl (3.48 g, 23.2 mmol) was added. The reaction mixture was stirred at 23 ° C for 4 h. 0.1 N HCl was added until a pH of 4-5 was reached and the reaction was extracted with CH ₂ Cl ₂ (2 x 150 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hex: EtOAc, from 10: 1 to 4: 1) to give compound 12a (8.47 g, 97%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.22 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.86 (m, 1H ), 5.07 (m, 2H), 4.41 (m, 2H), 4.29 (br s, 1H), 3.88 (m, 1H), 3.80 (s, 3H), 3, 74 (m, 1H), 3.62 (m, 2H), 3.48 (m, 1H), 3.34 (d, J = 6.8 Hz, 2H), 3.17 (d, J = 4 , 9Hz, 1H), 2.55 (d, J = 9.2Hz, 1H), 2.26 (m, 1H), 1.78 (m, 2H), 1.32 (s, 3H), 1.06 (d, J = 6.6Hz, 3H), 0.92 (s, 9H), 0.88 (s, 9H), 0.87 (s, 9H), 0.16 (s, 3H ), 0.10 (s, 3H), 0.05 (s, 3H), 0.03 (s, 9H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 159.4, 138.0, 130.5, 129.2, 117.1, 114.0, 77.4, 73.1, 72.8, 69.4 , 65.0, 64.8, 64.5, 60.7, 55.4, 51.9, 46.9, 33.7, 29.9, 26.3, 26.2, 26.1, 18 , 6, 18.5, 18.1, 15.1, 13.5, -4.3, -5.0, -5.1, -5.2.
MS (ESI) m / z: 775 (M + 23) ⁺ , 753 (M + 1) ⁺ .
[α] ²⁵ _D + 3.0 (c 0.54, CH ₂ Cl ₂ ).
R _f = 0.66 (Hex: EtOAc, 4: 1).

Example 13: Compound 12b

To a solution of 12a (500 mg, 0.663 mmol) in CH ₂ Cl ₂ (30 mL) was added Dess-Martin periodinane (562 mg, 1.32 mmol) at 23 ° C. the reaction mixture was stirred at 23 ° C for 3 h. Then a saturated aqueous solution of NaHCO ₃ (30 mL) was added and the mixture extracted with CH ₂ Cl ₂ (3 x 40 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 10: 1) to give compound 12b (414 mg, 83%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.24 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 5.78 (m, 1H ), 5.23 (m, 2H), 4.42 (dd, J = 16.2, 11.4 Hz, 2H), 4.02 (dd, J = 10.2, 4.8 Hz, 1H) , 3.81 (s, 3H), 3.74 (m, 1H), 3.61 (m, 2H), 3.33 (m, 3H), 2.48 (d, J = 9.3 Hz, 1H), 1.77 (m, 1H), 1.29 (s, 3H), 1.06 (d, J = 6.6Hz, 3H), 0.87 (s, 9H), 0.86 ( s, 9H), 0.84 (s, 9H), 0.11 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H), -0.01 (s, 3H), -0.03 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 209.2, 159.1, 134.3, 130.2, 129.0, 119.3, 113.7, 77.5, 72.7, 72.2 , 64.3, 63.0, 62.3, 62.2, 61.1, 55.9, 55.2, 33.6, 29.7, 26.0, 25.9, 25.8, 18 , 2, 18.1, 15.0, 12.2, -4.5, -5.2, -5.3, -5.4, -5.4, -5.5.
MS (ESI) m / z: 773 (M + 23) ⁺ .

Example 14: Compound 12c

To a solution of 12a (1.5 g, 1.99 mmol) in CH ₂ Cl ₂ (30 mL) at 0 ° C was Et ₃ N (5.55 mL, 39.82 mmol), DMAP (24 mg, 0.119 mmol) and Ac ₂ O (1.88 mL, 19.91 mmol). The reaction solution was stirred at 23 ° C for 12 h. Then a saturated aqueous solution of NaHCO ₃ (50 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (3 x 30 mL). The organic phases were washed with 0.1 N HCl, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 10: 1) to give compound 12c (1.12 g, 71%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.23 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 5.66 (m, 1H ), 5.48 (m, 2H), 5.09 (m, 2H), 4.42 (m, 2H), 3.80 (s, 3H), 3.60 (m, 2H), 3.46 (m, 2H), 3.34 (m, 4H), 2.61 (m, 1H), 2.48 (d, J = 9.1Hz, 1H), 1.95 (s, 3H), 1 , 77 (m, 1H), 1.34 (s, 3H), 1.06 (d, J = 6.6 Hz, 3H), 0.91 (s, 9H), 0.88 (s, 9H) , 0.86 (s, 9H), 0.11 (s, 3H), 0.05 (s, 3H), 0.03 (s, 6H), 0.01 (s, 3H), 0.01 ( s, 3H).
¹ H NMR (75 MHz, CDCl ₃₎ δ 169.8, 159.4, 136.7, 130.6, 129.3, 118.3, 114.0, 76.9, 73.0, 72.6 , 70.6, 64.4, 59.9, 55.4, 52.5, 47.1, 33.4, 26.3, 26.1, 26.1, 21.4, 18, 6, 18 , 3, 15.2, 13.3, -4.1, -4.9, -5.0, -5.1, -5.2, -5.2.
MS (ESI) m / z: 817 (M + 23) ⁺ , 812 (M + 18) ⁺ .
R _f = 0.63 (Hex: EtOAc, 4: 1).

Example 15: Compound 12d

To a solution of 12a (215 mg, 0.285 mmol) in THF (5 mL) at 0 ° C was added Py (0.46 mL, 5.7 mmol), DMAP (53 mg, 0.427 mmol) and (CF ₃ CO). ₂ O (0.40 mL, 2.85 mmol) was added. The reaction mixture was stirred at 23 ° C for 12 h. Then a saturated aqueous solution of NaHCO ₃ (7 mL) was added and the reaction mixture extracted with CH ₂ Cl ₂ (3 x 10 mL). The combined organic phases were washed with 0.1 N HCl (2 × 4 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 18: 1) to give compound 12d (221 mg, 91%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.22 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.75 (m, 1H ), 5.65 (m, 1H), 5.09 (m, 2H), 4.42 (s, 2H), 3.81 (s, 3H), 3.47 (m, 8H), 2.78 (m, 1H), 2.51 (d, J = 9.0Hz, 1H), 2.11 (m, 1H), 1.78 (m, 1H), 1.33 (s, 3H), 1 , 06 (d, J = 6.9 Hz, 3H), 0.91 (s, 9H), 0.88 (s, 18H), 0.12 (s, 3H), 0.06 (s, 3H) , 0.03 (s, 3H), 0.01 (s, 6H), 0.00 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 159.2, 156.0 (d, J _CF = 41.0 Hz), 134.6, 130.2, 129.1, 119.4, 113.8, 76.0, 75.4, 72.9, 72.7, 64.3, 64.0, 63.8, 59.3, 55.2, 51.6, 46.2, 33.1, 26, 1, 25.9, 18.3, 18.0, 14.8, 14.1, 13.2, -4.5, -5.0, -5.4, -5.5, -5.6 , -5,7.
MS (ESI) m / z: 866 (M + 18) ⁺ .
R _f = 0.45 (Hex: EtOAc, 4: 1).

Example 16: Compound 12e

The title compound was prepared from 11b (0.7 g, 1.09 mmol) as described above in Example 12. Chromatography (SiO ₂ Hex: EtOAc, 15: 1) gave 12e (661 g, 80%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.22 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.95 to 5.82 (m, 1H), 5.13-5.03 (m, 2H), 4.41 (dd, J = 15.6, 11.7Hz, 2H) 4.30-4.26 (m, 1H) , 3.86 (dd, J = 13.8, 3.6 Hz, 1H), 3.79 (s, 3H), 3.74 (dd, J = 10.5, 6.3 Hz, 1H), 3.64 (d, J = 5.7 Hz, 1H), 3.61 (d, J = 6.3 Hz, 1H), 3.50 (dd, J = 9.9, 5.1 Hz, 1H ), 3.34 (d, J = 7.5 Hz, 2H), 3.18 (d, J = 4.8 Hz, 1H), 2.56 (d, J = 9.0 Hz, 1H), 2.32-2.23 (m, 1H), 1.85-1.79 (m, 1H), 1.74-1.71 (m, 1H), 1.31 (s, 3H), 1, 06 (d, J = 6.9 Hz, 3H), 0.97 (t, J = 7.5 Hz, 9H), 0.89 (s, 9H), 0.88 (s, 9H), 0, 68 (J = 7.2 Hz), 0.05 (s, 3H), 0.04 (s, 6H), 0.03 (s, 3H). ¹³ C NMR (75 MHz, CDCl ₃₎ δ 158.9, 137.6, 130.0, 128.8, 116.6, 113.5, 77.0, 72.6, 72.4, 69.1 , 64.7, 64.6, 64.0, 60.2, 54.9, 51.3, 46.2, 33.3, 25.7, 25.6, 18.0, 17.7, 14 , 7, 12.9, 6.7, 4.5, -5.5, -5.7.
MS (ESI) m / z: 775 (M + 23) ⁺ , 773 (M + 1) ⁺
R _f = 0.6 (Hex: EtOAc, 4: 1).

Example 17: Compound 12f

To a solution of 11a (500 mg, 0.78 mmol) in CH ₂ Cl ₂ (10 mL) at 0 ° C was added DIPEA (327 μL, 1.87 mmol) and MEMCl (107 μL, 0.94 mmol) , The reaction solution was stirred at 23 ° C for 14 h. Then the reaction was extracted with 0.1 N HCl (10 mL) and the organic phase was dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc 10: 1) to give Compound 12f (445 mg, 78%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.22 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.92 to 5.79 (m, 1H), 5.16-5.09 (m, 2H), 4.67 (s, 2H), 4.42 (dd, J = 15.3, 11.7Hz, 2H), 4, 23-4.18 (m, 1H), 4.85 (dd, J = 10.5, 4.8Hz, 1H), 3.80 (s, 3H), 3.67-3.64 (m, 2H), 3.60 (d, J = 5.7Hz, 2H), 3.57-3.51 (m, 2H), 3.49-3.40 (m, 2H), 3.37 (3 , 3H), 2.56 (d, J = 9.3 Hz, 1H), 2.45-2.40 (m, 1H), 1.85-1.77 (m, 1H), 1.74- 1.72 (m, 1H), 1.30 (s, 3H), 1.06 (d, J = 6.6Hz, 3H), 0.91 (s, 9H), 0.87 (s, 9H ), 0.15 (s, 3H), 0.09 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H).
MS (ESI) m / z: 749 (M + 23) ⁺ .
R _f = 0.25 (Hex: EtOAc, 4: 1).

Example 18: Compound 12g

To a solution of 12f (438 mg, 0.6 mmol) in CH ₂ Cl ₂ (10 mL) at 0 ° C was Et ₃ N (1.67 mL, 12 mmol), DMAP (74 mg, 0.6 mmol ) and Ac ₂ O (567 μL, 6 mmol). The reaction mixture was stirred at 23 ° C for 12 h. Then the reaction mixture was extracted with 0.1 N HCl (10 mL) and the organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 7: 1) to give compound 12g (343mg, 74%) as a colorless oil. ¹ H NMR (300 MHz, CDCl ₃₎ δ 7.23 (d, J = 8.1 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.74 (dt, J = 19.8, 9.9 Hz, 1H), 5.52-5.49 (m, 1H), 5.13-5.07 (m, 2H), 4.65 (s, 2H), 4, 42 (dd, J = 13.5, 12.0 Hz, 2H), 3.80 (s, 3H), 3.66-3.62 (m, 2H), 3.60-3.57 (m, 1H), 3.54-3.47 (m, 4H), 3.40-3.34 (m, 1H), 3.38 (s, 3H), 3.28 (d, J = 5.7 Hz , 1H), 2.81-2.76 (m, 1H), 2.48 (d, J = 8.7 Hz, 1H), 1.97 (s, 3H), 1.83-1.73 ( m, 1H), 1.56 (bs, 1H), 1.31 (s, 3H), 1.07 (d, J = 6.9 Hz, 3H), 0.91 (s, 9H), 0, 88 (s, 9H), 0.12 (s, 3H), 0.06 (s, 3H), 0.03 (s, 6H).
MS (ESI) m / z: 791 (M + 23) ⁺ .
R ₁ = 0.26 (Hex: EtOAc, 4: 1).

Example 19: Compound 12h

To a solution of 11a (75 mg, 0.117 mmol) in CH ₂ Cl ₂ (3 mL) at 0 ° C was added DIPEA (82 μL, 0.47 mmol) and TESCl (40 μL, 0.234 mmol). The reaction mixture was stirred at 23 ° C for 3 h. Then 0.1N HCl was added until pH = 4-5 was reached and the reaction mixture was extracted with CH ₂ Cl ₂ (2 x 10 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 12: 1) to give compound 12h (77 mg, 87%) as a pale yellow oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.22 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 5.94 to 5.82 (m, 1H), 5.11 (dd, J = 9.9, 2.1Hz, 1H), 5.08 (dd, J = 16.8, 2.1Hz, 1H), 4.41 ( dd, J = 17.1, 11.7 Hz, 2H), 4.33-4.29 (m, 1H), 3.87 (dd, 1H), 3.80 (s, 3H), 3.65 -3.60 (m, 2H), 3.49 (dd, J = 9.9, 5.1 Hz, 1H), 3.33 (d, J = 6.9 Hz, 2H), 3.24 ( d, J = 4.5Hz, 1H), 2.56 (d, J = 9.3Hz, 1H), 2.30-2.25 (m, 1H), 1.82-1.75 (m , 2H), 1.31 (s, 3H), 1.03 (d, J = 6.6 Hz, 3H), 0.93-0.90 (m, 9H), 0.92 (s, 9H) , 0.87 (s, 9H), 0.57 (q, J = 7.8Hz, 6H), 0.16 (s, 3H), 0.10 (s, 3H), 0.07 (s, 3H), 0.05 (s, 3H).
MS (ESI) m / z: 775 (M + 23) ⁺ .
R _f = 0.58 (Hex: EtOAc, 4: 1).

Example 20: Compound 12i

To a solution of 11a (128 mg, 0.2 mmol) in CH ₂ Cl ₂ (10 mL) at 23 ° C was added DIPEA (104 μL, 0.6 mmol), DMAP (2 mg, 0.02 mmol), and SEMCl (53 μL, 0.3 mmol) was added. The reaction mixture was stirred at 23 ° C for 6 h. Then 0.1 N HCl was added until a pH of 4-5 was reached and the reaction mixture was extracted with CH ₂ Cl ₂ (2 x 20 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 10: 1) to give compound 12i (142 mg, 92%) as a pale yellow oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.22 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 5.79 to 5.88 (m, 1H), 5.10-5.17 (m, 2H), 4.61 (s, 2H), 4.42 (dd, J = 15.9, 11.5Hz, 2H), 4, 17-4.22 (m, 1H), 3.76-3.87 (m, 1H), 3.79 (s, 3H), 3.42-3.62 (m, 3H), 3.36 (d, J = 6.8Hz, 1H), 2.56 (d, J = 9.3Hz, 1H), 2.40-2 , 45 (m, 1H), 1.72-1.83 (m, 2H), 1.25 (s, 3H), 1.06 (d, J = 6.6 Hz, 3H), 0.19 ( s, 9H), 0.87 (s, 9H), 0.15 (s, 3H), 0.09 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H), 0.00 (s, 9H).
¹³ C NMR (75 MHz, CDCl ₃ ): d 159.4, 137.8, 130.4, 129.3, 117.4, 114.0, 95.2, 73.1, 72.8, 70, 3, 69.4, 65.3, 64.8, 64.2, 60.6, 55.4, 49.2, 47.0, 33.8, 29.9, 26.3, 26.0, 18.5, 18.3, 18.1, 15.1, 13.7, -1.2, -4.2, -5.1, -5.2.
MS (ESI) m / z: 792 (M + 23) ⁺
R _f = 0.56 (hexane: EtOAc, 4: 1).

Example 21: Compound 12j

To a solution of 11a (600 mg, 0.93 mmol) in CH ₂ Cl ₂ (10 mL) at 0 ° C was Et ₃ N (2.61 mL, 18.76 mmol), DMAP (115 mg, 0). 93 mmol) and Ac ₂ O (887 μL, 9.39 mmol) were added. The reaction mixture was stirred at 23 ° C for 3 h. Then 0.1 N HCl was added until a pH of 4-5 was reached and the reaction mixture was extracted with CH ₂ Cl ₂ (2 x 20 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hex: EtOAc, from 10: 1 to 5: 1) to give compound 12j (592 mg, 87%) as a pale yellow oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.22 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.72 to 5.60 (m, 1H), 5.53-5.50 (m, 1H), 5.16-5.07 (m, 2H), 4.42 (s, 2H), 4.03 (dd, J = 11 , 1, 6.3 Hz, 1H), 3.90 (dd, J = 11.1, 6.9 Hz, 1H), 3.80 (s, 3H), 3.58 (dd, J = 10, 2, 5.7 Hz, 1H), 3.47 (dd, J = 10.2, 6.3 Hz, 1H), 3.38-3.34 (m, 3H), 2.88-2.83 (m, 1H), 2.48 (d, J = 9.3Hz, 1H), 2.01 (s, 3H), 1.98 (s, 3H), 1.95-1.90 (m, 1H), 1.83-1.74 (m, 1H), 1.32 (s, 3H), 1.06 (d, J = 6.6Hz, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.12 (s, 3H), 0.06 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H).
MS (ESI) m / z: 745 (M + 23) ⁺ .
R _f = 0.34 (Hex: EtOAc, 4: 1).

Example 22: Compound 12k

To a solution of crude product 12e (545 mg, 0.73 mmol) in a mixture of CH ₂ Cl ₂ : H ₂ O (8: 0.4 mL) at 23 ° C was added 2,3-dichloro-5,6- dicyano-1,4-benzoquinone (329 mg, 1.45 mmol). The reaction mixture was stirred at 23 ° C for 45 min. A saturated aqueous solution of NaHCO ₃ (30 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (3 x 40 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in MeOH and NaBH ₄ (70 mg, 1.9 mmol) was added.

The mixture was stirred at 23 ° C for 2 h and then the reaction mixture was concentrated under reduced pressure. A saturated aqueous solution of NaHCO ₃ (20 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (3 x 30 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 10: 1) to give compound 12k (300 mg, 65%) as a pale yellow oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 5.88 to 5.80 (m, 1H), 5.15 to 5.09 (m, 2H), 4.18 to 4.17 (m, 1H), 3.92 (dd, J = 10.5, 4.5Hz, 1H), 3.86-3.68 (m, 1H), 3.66-3.56 (m, 3H), 3.50- 3.47 (m, 1H), 3.33 (d, J = 3.9Hz, 1H), 2.54 (d, J = 9.3Hz, 1H), 2.38-2.34 (m , 1H), 1.87-1.86 (m, 1H), 1.71-1.62 (m, 1H), 1.33 (s, 3H), 1.03 (d, J = 6.9 Hz, 3H), 0.95 (t, J = 8.1 Hz, 9H), 0.87 (s, 9H), 0.87 (s, 9H), 0.67 (q, J = 8.4 Hz, 6H), 0.05 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H).
MS (ESI) m / z: 655 (M + 23) ⁺ , 633 (M + 1) ⁺ .
R _f = 0.38 (Hex: EtOAc, 4: 1).

Example 23: Compound 121

To a solution of 12e (100 mg, 0.13 mmol) in CH ₂ Cl ₂ (6 mL) was added Dess-Martin periodinane (113 mg, 0.26 mmol) and a catalytic amount of NaHCO ₃ at 23 ° C. The reaction mixture was stirred at 23 ° C for 2 h. A saturated aqueous solution of NaHCO ₃ (10 mL) was added and the mixture extracted with CH ₂ Cl ₂ (3 x 10 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 20: 1) to give Compound 121 (110 mg, 96%) as a pale yellow oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.27 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 5.78 (ddd, J = 16.8, 10.2, 9.0 Hz, 1H), 5.29-5.22 (m, 2H), 4.43 (q, J = 11.4 Hz, 2H), 4.04 ( dd, J = 10.2, 4.2Hz, 1H), 3.84 (s, 3H), 3.77-3.72 (m, 1H), 3.66-3.60 (m, 2H) , 3.45-3.30 (m, 5H), 2.50 (d, J = 9.3Hz, 1H), 1.85-1.75 (m, 1H), 1.32 (s, 3H ), 1.09 (d, J = 6.6 Hz, 1H), 0.95 (t, J = 7.8 Hz, 9H), 0.91 (s, 9H), 0.87 (s, 9H ), 0.63 (q, J = 7.8 Hz, 6H), 0.08 (s, 3H), 0.07 (s, 3H), 0.01 (s, 3H), 0.00 (s , 3H). ¹³ C NMR (75 MHz, CDCl ₃₎ δ 209.9, 159.1, 134.3, 130.2, 129.0, 119.3, 113.7, 78.0, 72.3, 72.1 , 64.8, 63.0, 62.6, 62.3, 61.1, 56.1, 55.2, 33.6, 29.7, 25.9, 25.8, 18.2, 18 , 1, 15.1, 11.9, 6.8, 4.6, -5.3, -5.4, -5.5.
MS (ESI) m / z: 773 (M + 23) ⁺
R _f = 0.57 (hexane: EtOAc, 4: 1).

Example 24: Compound 12m

To a solution of 12k (280 mg, 0.44 mmol) in THF (5 mL) at 0 ° C was added Et ₃ N (368 μL, 2.64 mmol), DMAP (5 mg, 0.04 mmol) and Ac ₂ O (125 μL, 1.32 mmol) was added. The reaction mixture was stirred at 23 ° C 1H. Then 0.1 N HCl was added until a pH of 4-5 was reached and the reaction mixture was extracted with CH ₂ Cl ₂ (2 x 10 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 15: 1) to give compound 12m (258mg, 87%) as a pale yellow oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 5.90 (ddd, J = 17.1, 10.8, 9.6 Hz, 1H), 5.16 to 5.09 (m, 2H), 4, 32-4.28 (m, 1H), 4.09 (dd, J = 11.1, 5.7 Hz, 1H), 3.89-3.76 (m, 3H), 3.70-3, 67 (m, 2H), 3.56 (dd, J = 9.9, 5.1 Hz, 1H), 3.08, (d, J = 4.5 Hz, 1H), 2.57 (d, J = 9.3 Hz, 1H), 2.40-2.31 (m, 1H), 2.05 (s, 3H), 1.30 (s, 3H), 1.10 (d, J = 6 , 9 Hz, 3H), 0.96 (t, J = 8.1 Hz, 9H), 0.88 (s, 9H), 0.87 (s, 9H), 0.69 (q, J = 8 , 1 Hz, 6H), 0.05 (s, 3H), 0.03 (s, 6H), 0.02 (s, 3H).
R _f = 0.66 (Hex: EtOAc, 4: 1).

Example 25: Compound 12n

To a solution of 11a (110 mg, 0.17 mmol) in CH ₂ Cl ₂ (5 mL) was added PhB (OH) ₂ (33 mg, 0.26 mmol) and the reaction mixture was stirred at 23 ° C for 1 h touched. Then the solution was filtered through celite. The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hex: EtOAc, from 20: 1 to 10: 1) to give compound 12a (94 mg, 75%) as a pale yellow oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.81 (dd, J = 7.8, 1.2 Hz, 2H), 7.65-7.60 (m, 1H), 7.56 to 7, 42 (m, 2H), 7.24 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 5.88 (ddd, J = 18.9, 10.2, 8.7 Hz, 1H), 5, 23-5.17 (m, 2H), 4.54 (dd, J = 6.6, 2.4 Hz, 1H), 4.39 (dd, J = 18.0, 11.1 Hz, 2H) , 4.27 (dd, J = 11.1, 3.3 Hz, 1H), 4.03 (brd, J = 0.5 Hz, 1H), 3.97 (dd, J = 10.2, 6 , 3 Hz, 1H), 3.82 (d, J = 5.1 Hz, 1H), 3.68 (s, 3H), 3.65 (dd, J = 10.5, 3.6 Hz, 1H ), 3.46-3.35 (m, 2H), 2.87 (brd, J = 8.4Hz, 1H), 2.70 (d, J = 9.3Hz, 1H), 1.93 -1.83 (m, 2H), 1.30 (s, 3H), 1.11 (d, J = 6.6 Hz, 3H), 0.95 (s, 9H), 0.92 (s, 9H), 0.18 (s, 3H), 0.14 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H).
R _f = 0.46 (Hex: EtOAc, 4: 1).

Example 26: Connection 120

The title compound was obtained as a precursor of 11a in the reduction reaction of 10a before treatment with H ₂ O ₂ . ¹ H NMR (300 MHz, CDCl ₃₎ δ 7.20 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 5.87 to 5.79 (m, 1H), 5.22-5.17 (m, 2H), 4.38 (dd, J = 10.8Hz, 13.2Hz, 2H), 4.30 (dd, J = 6, 6, 2.7 Hz, 1H), 4.07 (dd, J = 10.8, 3.0 Hz, 1H), 3.83-3.72 (m, 2H), 3.80 (s, 3H ), 3.69 (d, J = 5.1 Hz, 1H), 3.50 (dd, J = 9.9, 3.0 Hz, 1H), 3.37-3.32 (m, 2H) , 2.67 (brd, J = 8.4 Hz, 1H), 2.62 (d, J = 9.3 Hz, 1H), 1.81-1.76 (m, 2H), 1.21 ( s, 3H), 1.06 (d, J = 6.9 Hz, 3H), 0.91 (s, 9H), 0.89 (s, 9H), 0.12 (s, 3H), 0, 05, (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 159.1, 134.0, 130.2, 129.1, 118.4, 113.7, 76.2, 72.9, 70.0, 67.1 , 64.8, 59.5, 55.2, 45.7, 43.9, 33.4, 26.4, 26.0, 25.9, 25.5, 18.2, 14.9, 14 , 0, 13.3, -4.3, -4.9, -5.3, -5.4.
MS (ESI) m / z: 661 (M + 23) ⁺
R _f = 0.50 (Hex: EtOAc, 4: 1).

Example 27: Compound 12p

To a solution of 11a (119 mg, 0.18 mmol) in THF (10 mL) was added CDI (49 mg, 0.3 mmol) and NaH (8 mg, 0.2 mmol) and the reaction mixture was at 23 ° C stirred for 3 h. Then a saturated aqueous solution of NaHCO3 (10 mL) was added and the mixture extracted with CH ₂ Cl ₂ (3 x 10 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 5: 1) to give compound 12p (97 mg, 78%) as a pale yellow oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.19 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 5.79 to 5.70 (m, 1H), 5.32-5.26 (m, 2H), 4.67 (dd, J = 7.5, 2.4Hz, 1H), 4.43 (dd, J = 10.5 , 3.6 Hz, 1H), 4.35 (q, J = 10.2 Hz, 2H), 4.25 (dd, J = 16.2, 15.3 Hz, 2H), 3.80 (s , 3H), 3.77-3.69 (m, 2H), 3.54 (dd, J = 10.5, 3.0 Hz, 1H), 3.42 (dd, J = 9.3, 4 , 8 Hz, 1H), 3.30 (t, J = 9.3 Hz, 1H), 2.92 (br d, J = 8.4 Hz, 1H), 2.66 (d, J = 9, 6Hz, 1H), 1.95-1.92 (m, 1H), 1.21 (s, 3H), 1.05 (d, J = 6.9Hz, 3H), 0.89 (s, 9H), 0.88 (s, 9H), 0.11 (s, 3H), 0.07 (s, 6H), 0.05 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 173.8, 159.4, 154.1, 130.5, 129.4, 114.0, 99.3, 76.5, 73.0, 72.6 , 68.0, 66.0, 64.7, 64.6, 63.6, 61.2, 59.5, 58.8, 55.4, 44.5, 42.1, 41.6, 33 , 7, 29.7, 28.8, 26.3, 26.3, 26.2, 26.1, 19.0, 18.6, 18.3, 18.2, 15.2, 14.9 , 13,7, -4,1, -4,2, -5,1, -5,2.
MS (ESI) m / z: 687 (M + 23) ⁺ .
R _f = 0.47 (Hex: EtOAc, 4: 1).

Example 28: Compound 12q

The title compound was obtained as a precursor of 11b in the reduction reaction of 10b before treatment with H ₂ O ₂ . ¹ H NMR (300 MHz, CDCl ₃₎ δ 7.16 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 5.86 to 5.74 (m, 1H), 5.20-5.15 (m, 2H), 4.40-4.34 (m, 2H), 4.18-4.15 (m, 1H), 4.09-4 , 03 (m, 1H), 3.85-3.79 (m, 1H), 3.76 (s, 3H), 3.66 (d, J = 7.8 Hz, 1H), 3.58 ( q, J = 7.2 Hz, 1H), 3.47 (dd, J = 9.9, 2.4 Hz, 1H), 3.37-3.27 (m, 1H), 2.87 (br d, J = 8.7 Hz, 1H), 2.74 (q, J = 7.5 Hz, 1H), 2.63 (d, J = 9.3 Hz, 1H), 1.72-1, 65 (m, 2H), 1.18 (s, 3H), 1.03 (d, J = 6.3 Hz, 3H), 0.91-0.85 (m, 9H), 0.84 (s , 9H), 0.60 (q, J = 7.8 Hz, 6H), -0.01 (s, 3H), -0.02 (s, 3H).
R _f = 0.65 (Hex: EtOAc, 4: 1).

Example 29: Compound 13a

Via a solution of 12a (5.91 g, 7.85 mmol) in CH ₂ Cl ₂ (80 mL) was passed for 15 min at -78 ° C, an O ₃ stream. Then, Ph ₃ P (6.29 g, 24 mmol) was added and the mixture was warmed to room temperature and stirred for 12 h. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 20: 1) to give compound 13a (4.99 g, 84%) as a white solid. ¹ H NMR (300 MHz, CDCl ₃₎ δ 9.80 (d, J = 3.0 Hz, 1H), 7.20 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.66 (m, 1H), 4.39 (s, 2H), 3.84 (m, 2H), 3.78 (s, 3H), 3.68 (m , 2H), 3.61 (m, 2H), 3.37 (m, 2H), 2.58 (d, J = 9.0 Hz, 1H), 2.44 (m, 1H), 1.82 (m, 1H), 1.72 (m, 1H), 1.29 (s, 3H), 1.05 (d, J = 6.6Hz, 3H), 0.91 (s, 9H), 0 , 87 (s, 9H), 0.85 (s, 9H), 0.15 (s, 3H), 0.11 (s, 3H), 0.06 (s, 6H), 0.00 (s, 6H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 205.3, 159.2, 130.0, 129.0, 113.7, 76.4, 72.8, 72.7, 67.9, 64.6 , 63.9, 60.8, 60.1, 57.7, 55.1, 44.4, 33.5, 26.1, 25.7, 18.3, 18.1, 17.8, 14 , 8, 12.9, -4.6, -5.3, -5.5, -5.5, -5.7, -5.7.
[α] ²⁵ _D + 2,3 (c 0,50, CH ₂ Cl ₂ ).
R _f = 0.46 (Hex: EtOAc, 4: 1).

Example 30: Compound 13b

To a solution of 12c (2.25 g, 2.84 mmol) in THF: H ₂ O (70:30, 105 mL) at 23 ° C was NMO (1.16 g, 9.94 mmol) and OsO ₄ (5.68 mL, 0.568 mmol, 0.1 M in ^t BuOH) was added and the reaction mixture was stirred at 23 ° C overnight. Florisil (16 g), NaHSO ₃ (16 g), and EtOAc (160 mL) were added and the mixture stirred vigorously for 30 minutes. The mixture was filtered through Celite and the filtrate concentrated to give the corresponding diol. This diol was dissolved in anhydrous toluene (50 mL) and at 0 ° C Pb (OAc) ₄ (1.57 g, 3.55 mmol) was added, stirred for 30 min, filtered through celite, washed with EtOAc and concentrated under reduced pressure Concentrated pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 20: 1) to give compound 13b (0.97 g, 43%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 9.61 (d, J = 3.9 Hz, 1H), 7.22 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 5.56 (dd, J = 10.3, 6.6 Hz, 1H), 4.42 (s, 2H), 3.95 (m, 1H), 3.80 (s, 3H), 3.54 (m, 2H), 3.38 (d, J = 7.0Hz, 2H), 3.24 (d, J = 6.8Hz, 1H), 3.04 (m, 1H), 2.49 (d, J = 9.0Hz, 1H), 1.98 (s, 3H), 1.79 (m, 1H), 1.31 (s, 3H), 1 , 06 (d, J = 6.8 Hz, 3H), 0.92 (s, 9H), 0.88 (s, 9H), 0.85 (s, 9H), 0.13 (s, 3H) , 0.06 (s, 6H), 0.04 (s, 3H), 0.03 (s, 6H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 203.3, 170.1, 159.4, 130.4, 129.3, 114.0, 76.6, 73.1, 72.7, 69.1 , 64.4, 63.9, 61.3, 60.0, 58.4, 55.4, 46.4, 33.4, 29.9, 26.4, 26.1, 26.0, 21 , 2, 18.6, 18.4, 18.3, 15.1, 12.8, -4.1, -5.0, -5.1, -5.2, -5,3, -5,4.
MS (ESI) m / z: 819 (M + 23) ⁺ .
R _f = 0.47 (hexane: EtOAc, 4: 1)

Example 31: Compound 13c

To a solution of 13a (90 mg, 0.12 mmol) in CH ₂ Cl ₂ (10 mL) at 0 ° C was added Py (0.19 mL, 2.4 mmol), DMAP (22 mg, 0.18 mmol ) and (CF ₃ CO) ₂ O (0.17 mL, 1.2 mmol) were added and the reaction mixture was stirred at 0 ° C for 2 h. Then the reaction mixture was concentrated under reduced pressure to give 13c, which was used without further purification in the subsequent stages. ¹ H NMR (300 MHz, CDCl ₃₎ δ 9.63 (d, J = 2.4 Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6Hz, 2H), 5.75-5.79 (m, 1H), 4.34-4.42 (m, 2H), 3.86-3.90 (m, 2H), 3, 78 (s, 3H), 3.48 (d, J = 5.4 Hz, 1H), 3.30-3.38 (m, 3H), 3.08-3.13 (m, 1H), 2 , 51 (d, J = 9.0 Hz, 1H), 2.21-2.27 (m, 1H), 1.77-1.82 (m, 1H), 1.25 (s, 3H), 1.05 (d, J = 6.8Hz, 3H), 0.91 (s, 9H), 0.86 (s, 9H), 0.85 (s, 9H), 0.13 (s, 3H ), 0.07 (s, 3H), 0.06 (s, 3H), 0.02 (s, 6H), 0.00 (s, 3H).
R _f = 0.70 (Hex: EtOAc, 4: 1).

Example 32: Compound 13d

According to the procedure described in Example 29, 12h (1 g, 1.32 mol) after purification of the crude product by flash column chromatography (Hex: EtOAc, 20: 1) was converted to 13d (715 mg, 72%, colorless oil).
¹ H NMR (300 MHz, CDCl ₃₎ δ 9.81 (d, J = 3.0 Hz, 1H), 7.21 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 4.70-4.64 (m, 1H), 4.40 (s, 2H), 3.89-3.81 (m, 1H), 3.80 (s, 3H), 3.75-3.66 (m, 2H), 3.64 (d, J = 6.6Hz, 2H), 3.38-3.35 (m, 2H), 2.60 (i.e. , J = 9.3 Hz, 1H), 2.50-2.46 (m, 1H), 1.85-1.80 (m, 1H), 1.77-1.68 (m, 1H), 1.29 (s, 3H), 1.06 (d, J = 6.6Hz, 3H), 0.94-087 (m, 9H), 0.92 (s, 9H), 0.87 (s , 9H), 0.55 (q, J = 7.8Hz, 6H), 0.16 (s, 3H), 0.11 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H).
MS (ESI) m / z: 777 (M + 23) ⁺ .
R _f = 0.5 (Hex: EtOAc, 4: 1).

Example 33: Compound 13e

According to the procedure described in Example 29, 12j (590 mg, 0.81 mol) after purification of the crude product by flash column chromatography (Hex: EtOAc, 10: 1) was converted to 13e (420 mg, 71%, pale yellow oil).
¹ H NMR (300 MHz, CDCl ₃₎ δ 9.58 (d, J = 20.0 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 5.58 (dd, J = 5.1, 4.6 Hz, 1H), 4.38 (s, 2H), 4.30-4.23 (m, 2H) , 3.76 (s, 3H), 3.50 (dd, J = 6.9, 5.1 Hz, 2H), 3.30 (d, J = 7.0 Hz, 2H), 3.25- 3.22 (m, 2H), 2.44 (d, J = 9.3Hz, 1H), 2.15-2.12 (m, 1H), 1.93 (s, 3H), 1.92 (s, 3H), 1.23 (s, 3H), 1.12 (d, J = 6.6Hz, 3H), 0.84 (s, 9H), 0.82 (s, 9H), 0 , 09 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H), 0.00 (s, 3H).
R _f = 0.26 (Hex: EtOAc, 4: 1).

Example 34: compound 13f

According to the procedure described in Example 29, 12 g (342 mg, 0.44 mol) after purification of the crude product by flash column chromatography (Hex: EtOAc, from 4: 1 to 0: 1) in 13f (306 mg, 90%, weak yellow oil).
¹ H NMR (300 MHz, CDCl ₃₎ δ 9.64 (d, J = 3.3 Hz, 1H), 7.22 (d, J = 8.1 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 5.64 (dd, J = 6.6, 3.9 Hz, 1H), 4.63 (s, 2H), 4.40 (s, 2H), 3.86 (dd, J = 9.9, 7.5Hz, 1H), 3.79 (s, 3H), 3.74 (dd, J = 10.2, 4.5Hz, 1H), 3.65- 3.61 (m, 2H), 3.53-3.50 (m, 4H), 3.85-3.34 (m, 1H), 3.37 (s, 3H), 3.21 (d, J = 7.2Hz, 1H), 3.15-3.13 (m, 1H), 2.48 (d, J = 9.0Hz, 1H), 1.98 (s, 3H), 1, 80-1.75 (m, 1H), 1.2S (s, 3H), 1.05 (d, J = 6.9Hz, 3H), 0.90 (s, 9H), 0.87 (s , 9H), 0.11 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H).
MS (ESI) m / z: 793 (M + 23) ⁺ .
R _f = 0.1 (Hex: EtOAc, 4: 1).

Example 35: Compound 13g

According to the procedure described in Example 29, 12m (200mg, 0.3mmol) after purification of the crude product by flash column chromatography (Hex: EtOAc, 15: 1) was converted to 13g (173mg, 86%, pale yellow oil).
¹ H NMR (300 MHz, CDCl ₃₎ δ 9.84 (d, J = 2.7 Hz, 1H), 4.67 to 4.61 (m, 1H), 4.08 (dd, J = 11, 1, 5.7 Hz, 1H), 3.95-3.84 (m, 3H), 3.81 (d, J = 5.1 Hz, 2H), 3.70 (d, J = 6.9 Hz, 1H), 3.47 (d, J = 5.4 Hz, 1H), 2.64-2.61 (m, 1H), 2.26 (d, J = 9.3 Hz, 1H), 2.04 (s, 3H), 1.85-1.80 (m, 1H), 1.30 (s, 3H), 1.11 (d, J = 6.6Hz, 3H), 0.96 (t, J = 8.1Hz, 9H), 0.87 (s, 9H), 0.85 (s, 9H), 0.68 (q, J = 8.1Hz, 6H), 0.07 (s, 3H), 0.06 (s, 3H), 0.03 (s, 6H).
MS (ESI) m / z: 699 (M + 23) ⁺ , 677 (M + 1) ⁺ .
R _f = 0.52 (Hex: EtOAc, 4: 1).

Example 36: Compounds 14a and 14b

14a: ¹H NMR (300 MHz, CDCl₃) δ 7,20 (d, J = 8,7 Hz, 2H), 6,85 (d, J = 8,7 Hz, 2H), 4,46-4,43 (m, 1H), 4,39 (s, 2H), 4,33 (m, 1H), 4,14 (d, J = 7,2 Hz, 1H), 3,92-3,88 (m, 2H), 3,83 (d, J = 3,6 Hz, 1H), 3,78 (s, 3H), 3,63 (s, 3H), 3,61-3,57 (m, 3H), 3,41-3,30 (m, 2H), 3,17 (s, 3H), 3,0-2,91 (m, 1H), 2,63-2,62 (m, 1H), 2,58 (d, J = 9,0 Hz, 1H), 2,02-1,96 (m, 1H), 1,85-1,78 (m, 1H), 1,75-1,72 (m, 1H), 1,27 (s, 3H), 1,06 (d, J = 6,6 Hz, 3H), 0,91 (s, 9H), 0,86 (s, 18H), 0,14 (s, 3H), 0,11 (s, 3H), 0,08 (s, 3H), 0,05 (s, 3H), 0,02 (s, 3H), 0,01 (s, 3H).
¹³C NMR (75 MHz, CDCl₃) δ 173,8, 159,4, 130,3, 129,3, 114,0, 76,3, 73,0, 72,6, 70,4, 70,1, 64,8, 64,0, 61,9, 61,4, 60,6, 55,4, 47,9, 44,4, 36,9, 34,0, 32,1, 29,9, 26,5, 26,4, 26,1, 26,0, 18,6, 18,3, 18,0, 15,3, 12,8, –4,3, –5,0, –5,1, –5,2, –5,4.
MS (ESI) m/z: 858 (M+1)⁺.
[α]²⁵ _D – 10,7 (c 0,5, CH₂Cl₂).

14b: ¹H NMR (300 MHz, CDCl₃) δ 7,17 (d, J = 8,4 Hz, 2H), 6,83 (d, J = 8,4 Hz, 2H), 4,52-4,51 (m, 1H), 4,45 (s, 3H), 4,37 (s, 2H), 4,28-4,23 (m, 1H), 3,91-3,88 (m, 1H), 3,81 (m, 1H), 3,76 (s, 3H), 3,64 (s, 3H), 3,61-3,52 (m, 3H), 3,48-3,43 (dd J = 10,5, 3,3 Hz, 1H), 3,38-3,35 (m, 2H), 3,15 (s, 3H), 2,84-2,79 (m, 1H), 2,57 (d, J = 9,0 Hz, 1H), 1,94-1,92 (m, 1H), 1,83-1,81 (m, 1H), 1,72-1,69 (m, 1H), 1,24 (s, 3H), 1,05 (d, J = 6,3 Hz, 3H), 0,89 (s, 9H), 0,86 (s, 9H), 0,85 (s, 9H), 0,13 (s, 3H), 0,08 (s, 3H), 0,07 (s, 3H), 0,04 (s, 3H), 0,01 (s, 3H), –0,01 (s, 3H).
¹³C NMR (75 MHz, CDCl₃) δ 174,8, 159,4, 130,3, 129,2, 113,9, 76,4, 73,0, 72,8, 69,2, 68,5, 64,9, 64,1, 61,4, 60,8, 60,1, 55,4, 47,8, 43,7, 34,1, 26,5, 26,3, 26,2, 26,1, 26,0, 25,9, 18,7, 18,2, 17,9, 15,2, 12,7, –4,6, –4,9, –5,0, –5,4, –5,5.
MS (ESI) m/z: 880 (M+23)⁺, 858 (M+1)⁺.
[α]²⁵ _D + 12,8 (c 0,50, CH₂Cl₂).
R_f = 0,44 (Hex:EtOAc, 2:1).To a solution of N-methoxy-N-methylacetamide (0.8 mL, 7.56 mmol) in THF (2 mL) at -78 ° C was added bis (trimethylsilyl) lithium amide (7.56 mL, 1.0 M in THF, 7.56 mmol) and the reaction mixture was stirred at -78 ° C for 1 h. Then a solution of 13a (1.61 g, 2.13 mmol) in THF (10 mL) was added over the previous solution and the reaction mixture was stirred for a further 1 h at -78 ° C. Subsequently, a saturated aqueous solution of NH ₄ Cl (50 mL) was added and the reaction mixture extracted with EtOAc (3 x 60 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hex: EtOAc, from 4: 1 to 2: 1) to give compounds 14a and 14b (25:75) as colorless oils (1.67 g, in total yield of 91%).

14a: ¹ H NMR (300 MHz, CDCl ₃₎ δ 7.20 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.46 to 4 , 43 (m, 1H), 4.39 (s, 2H), 4.33 (m, 1H), 4.14 (d, J = 7.2Hz, 1H), 3.92-3.88 ( m, 2H), 3.83 (d, J = 3.6Hz, 1H), 3.78 (s, 3H), 3.63 (s, 3H), 3.61-3.57 (m, 3H 3.41-3.30 (m, 2H), 3.17 (s, 3H), 3.0-2.91 (m, 1H), 2.63-2.62 (m, 1H), 2.58 (d, J = 9.0 Hz, 1H), 2.02-1.96 (m, 1H), 1.85-1.78 (m, 1H), 1.75-1.72 ( m, 1H), 1.27 (s, 3H), 1.06 (d, J = 6.6 Hz, 3H), 0.91 (s, 9H), 0.86 (s, 18H), 0, 14 (s, 3H), 0.11 (s, 3H), 0.08 (s, 3H), 0.05 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H ).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 173.8, 159.4, 130.3, 129.3, 114.0, 76.3, 73.0, 72.6, 70.4, 70.1 , 64.8, 64.0, 61.9, 61.4, 60.6, 55.4, 47.9, 44.4, 36.9, 34.0, 32.1, 29.9, 26 , 5, 26.4, 26.1, 26.0, 18.6, 18.3, 18.0, 15.3, 12.8, -4.3, -5.0, -5.1, -5.2, -5.4.
MS (ESI) m / z: 858 (M + 1) ⁺ .
[α] ²⁵ _D - 10.7 (c 0.5, CH ₂ Cl ₂ ).

14b: ¹ H NMR (300 MHz, CDCl ₃₎ δ 7.17 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 4.52 to 4 , 51 (m, 1H), 4.45 (s, 3H), 4.37 (s, 2H), 4.28-4.23 (m, 1H), 3.91-3.88 (m, 1H ), 3.81 (m, 1H), 3.76 (s, 3H), 3.64 (s, 3H), 3.61-3.52 (m, 3H), 3.48-3.43 ( dd J = 10.5, 3.3 Hz, 1H), 3.38-3.35 (m, 2H), 3.15 (s, 3H), 2.84-2.79 (m, 1H), 2.57 (d, J = 9.0 Hz, 1H), 1.94-1.92 (m, 1H), 1.83-1.81 (m, 1H), 1.72-1.69 ( m, 1H), 1.24 (s, 3H), 1.05 (d, J = 6.3 Hz, 3H), 0.89 (s, 9H), 0.86 (s, 9H), 0, 85 (s, 9H), 0.13 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.04 (s, 3H), 0.01 (s, 3H ), -0.01 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 174.8, 159.4, 130.3, 129.2, 113.9, 76.4, 73.0, 72.8, 69.2, 68.5 , 64.9, 64.1, 61.4, 60.8, 60.1, 55.4, 47.8, 43.7, 34.1, 26.5, 26.3, 26.2, 26 , 1, 26.0, 25.9, 18.7, 18.2, 17.9, 15.2, 12.7, -4.6, -4.9, -5.0, -5.4 , -5.5.
MS (ESI) m / z: 880 (M + 23) ⁺ , 858 (M + 1) ⁺ .
[α] ²⁵ _D + 12.8 (c 0.50, CH ₂ Cl ₂ ).
R _f = 0.44 (Hex: EtOAc, 2: 1).

Example 37: Compounds 14c and 14d

14c: ¹H NMR (300 MHz, CDCl₃) δ 7,28-7,39 (m, 5H), 7,19 (d, J = 8,7 Hz, 2H), 6,82 (d, J = 8,7 Hz, 2H), 5,20 (s, 2H), 5,17 (s, 2H), 4,58-4,64 (m, 1H), 4,38 (s, 2H), 3,78 (s, 3H), 3,58-3,82 (m, 4H), 3,50 (s, 2H), 3,28-3,41 (m, 3H), 2,60 (dd, J = 15,0 und 9,6 Hz, 1H), 2,53 (d, J = 9,3 Hz, 1H), 2,25 (dd, J = 153, 4,7 Hz, 1H), 1,76-1,86 (m, 1H), 1,59-1,62 (m, 1H), 1,26 (s, 3H), 1,05 (d, J = 6,6 Hz, 3H), 0,91 (s, 9H), 0,88 (s, 9H), 0,17 (s, 3H), 0,11 (s, 3H), 0,05 (s, 3H), 0,04 (s, 3H).
R_f = 0,33 (Hex:EtOAc, 4:1).

14d: ¹H NMR (300 MHz, CDCl₃) δ 7,32-7,55 (m, 5H), 7,20 (d, J = 8,7 Hz, 2H), 6,84 (d, J = 8,7 Hz, 2H), 5,19 (s, 2H), 4,43-4,48 (m, 1H), 4,40 (s, 2H), 4,32-4,40 (m, 1H), 4,19-4,23 (m, 1H), 3,81 (s, 3H), 3,75-3,98 (m, 3H), 3,42-3,64 (m, 3H), 3,39 (d, J = 7,8 Hz, 2H), 2,60 (d, J = 9,3 Hz, 1H), 2,61-2,79 (m, 1H), 1,78-1,93 (m, 2H), 1,74-1,77 (m, 1H), 1,25 (s, H), 1,05 (d, J = 6,7 Hz, 3H), 0,92 (s, 9H), 0,88 (s, 9H), 0,82-0,92 (m, 6H), 0,49-0,60 (m, 12H), 0,09 (s, 3H), 0,05 (s, 3H), 0,04 (s, 3H), 0,03 (s, 3H).
MS (ESI) m/z: 927 (M+23)⁺
R_f = 0,30 (Hex:EtOAc, 4:1).To a solution of benzyl acetate (38 μL, 0.53 mmol) in dry THF (5 mL) at -78 ° C was added lithium bis (trimethylsilyl) amide (264 μL, 1.0 M in THF, 0.264 mmol) and the reaction mixture was stirred at -78 ° C for 1 h. Then a solution of 13a (150 mg, 0.17 mmol) in THF (5 mL) was added over the previous solution and the reaction mixture was stirred at -78 ° C for 5 h. Subsequently, a saturated aqueous solution of NH ₄ Cl (30 mL) was added and the crude product extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hex: EtOAc, from 20: 1 to 5: 1) to give 14c (34 mg, 20%) and 14d (77 mg, 44%) as colorless oils.

14c: ¹ H NMR (300 MHz, CDCl ₃₎ δ 7.28-7.39 (m, 5H), 7.19 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 5.20 (s, 2H), 5.17 (s, 2H), 4.58-4.64 (m, 1H), 4.38 (s, 2H), 3, 78 (s, 3H), 3.58-3.82 (m, 4H), 3.50 (s, 2H), 3.28-3.41 (m, 3H), 2.60 (dd, J = 15.0 and 9.6 Hz, 1H), 2.53 (d, J = 9.3 Hz, 1H), 2.25 (dd, J = 153, 4.7 Hz, 1H), 1.76- 1.86 (m, 1H), 1.59-1.62 (m, 1H), 1.26 (s, 3H), 1.05 (d, J = 6.6Hz, 3H), 0.91 (s, 9H), 0.88 (s, 9H), 0.17 (s, 3H), 0.11 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H) ,
R _f = 0.33 (Hex: EtOAc, 4: 1).

14d: ¹ H NMR (300 MHz, CDCl ₃₎ δ 7.32 to 7.55 (m, 5H), 7.20 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7Hz, 2H), 5.19 (s, 2H), 4.43-4.48 (m, 1H), 4.40 (s, 2H), 4.32-4.40 (m, 1H 4,19-4,23 (m, 1H), 3,81 (s, 3H), 3,75-3,98 (m, 3H), 3,42-3,64 (m, 3H), 3.39 (d, J = 7.8Hz, 2H), 2.60 (d, J = 9.3Hz, 1H), 2.61-2.79 (m, 1H), 1.78-1 , 93 (m, 2H), 1.74-1.77 (m, 1H), 1.25 (s, H), 1.05 (d, J = 6.7 Hz, 3H), 0.92 ( s, 9H), 0.88 (s, 9H), 0.82-0.92 (m, 6H), 0.49-0.60 (m, 12H), 0.09 (s, 3H), 0 , 05 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H).
MS (ESI) m / z: 927 (M + 23) ⁺
R _f = 0.30 (Hex: EtOAc, 4: 1).

Example 38: Compound 15a

To a solution of 14a (1.09 g, 1.26 mmol) in CH ₂ Cl ₂ (20 mL) at 0 ° C was added 2,6-lutidine (443 μL, 3.8 mmol) and TBSOTf (437 μL, 1.9 mmol) was added. The reaction mixture was stirred at 0 ° C for 40 min. Then, a saturated aqueous solution of NH ₄ Cl (30 mL) was added and the reaction extracted with CH ₂ Cl ₂ (2 x 15 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hex: EtOAc, from 20: 1 to 4: 1) to give compound 15a (1.05 g, 85%) as a pale yellow oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.23 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 4.87 to 4.83 (m, 1H), 4.48-4.37 (m, 2H), 4.17-4.14 (m, 2H), 3.86 (dd, J = 10.2, 7.0 Hz, 1H ), 3.80 (s, 3H), 3.66 (s, 3H), 3.64-3.63 (m, 1H), 3.54 (dd, J = 10.2, 3.6 Hz, 1H), 3.53 (dd, J = 9.0, 5.1 Hz, 1H), 3.35-3.29 (m, 2H), 3.17 (s, 3H), 3.11-3 , 05 (m, 1H), 2.56-2.55 (m, 1H), 2.52 (d, J = 8.1 Hz, 1H), 2.31-2.28 (m, 1H), 1.84-1.82 (m, 1H), 1.81-1.78 (m, 1H), 1.29 (s, 3H), 1.09 (d, J = 6.6Hz, 3H) , 0.92 (s, 9H), 0.89 (s, 9H), 0.88 (s, 9H), 0.87 (s, 9H), 0.15 (s, 6H), 0.1 ( s, 3H), 0.09 (s, 3H), 0.06 (s, 3H), 0.04 (s, 6H), 0.02 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 173.4, 159.4, 130.4, 129.4, 114.0, 76.0, 72.9, 72.4, 69.5, 68.8 , 64.6, 64.1, 61.4, 61.0, 59.3, 55.4, 50.1, 43.6, 34.3, 29.9, 26.5, 26.2, 26 , 1, 26.0, 18.7, 18.3, 17.9, 15.4, 12.7, -4.4, -4.5, -4.6, -4.9, -5, 0, -5.2, -5.4, -5.5.
MS (ESI) m / z: 994 (M + 23) ⁺ , 972 (M + 1) ⁺ .
[α] ²⁵ _D - 20.0 (c 0.5, CH ₂ Cl ₂ ).
R _f = 0.43 (Hex: EtOAc, 4: 1).

Example 39: Compound 15b

According to the procedure described in Example 38, 14b (2.18 g, 2.52 mmol) was purified after purification of the crude product by flash column chromatography (Hex: EtOAc, 10: 1) in 15b (2.02 g, 82%, white solid ).
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.20 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 4.85 to 4.82 (m, 1H), 4.44-4.35 (m, 2H), 4.09 (t, J = 9.0Hz, 1H), 3.80 (s, 3H), 3.77-3, 73 (m, 1H), 3.65 (s, 3H), 3.63-3.60 (m, 1H), 3.42-3.30 (m, 3H), 3.15 (s, 3H) , 2.75-2.72 (m, 1H), 2.61 (d, J = 9.3Hz, 1H), 2.48 (dd, J = 15.3, 2.1Hz, 1H), 1.93-1.88 (m, 1H), 1.84-1.81 (m, 1H), 1.77-1.74 (m, 1H), 1.27 (s, 3H), 1, 08 (d, J = 6.6 Hz, 3H), 0.90 (s, 3H), 0.88 (s, 18H), 0.85 (s, 9H), 0.13 (s, 3H), 0.09 (s, 3H), 0.08 (s, 6H), 0.04 (s, 3H), 0.03 (s, 3H), 0.01 (s, 6H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 173.3, 159.4, 130.4, 129.4, 114.0, 76.0, 72.9, 69.5, 68.8, 64.6 , 64,1, 61,3, 61,1, 59,3, 55,4, 50,1, 43,5, 34,3, 29,9, 26,5, 26,2, 26,1, 26 , 0, 18.7, 18.3, 18.2, 17.9, 15.4, 12.7, -4.4, -4.5, -4.6, -4.9, -5, 0th
MS (ESI) m / z: 994 (M + 23) ⁺ , 972 (M + 1) ⁺ .
[α] ²⁵ _D + 23.1 (c 0.50, CH ₂ Cl ₂ ).
R _f = 0.37 (Hex: EtOAc, 4: 1).

Example 40: Compound 16a

To a solution of 15a (184 mg, 0.189 mmol) in CH ₂ Cl ₂ (5 mL) was added Dess-Martin periodinane (325 mg, 0.76 mmol) and a catalytic amount of NaHCO ₃ at 23 ° C. The reaction mixture was de stirred at 23 ° C for 3 h. A saturated aqueous solution of NaHCO ₃ (20 mL) was added and the mixture extracted with CH ₂ Cl ₂ (3 x 30 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 10: 1) to give compound 16a (150 mg, 81%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.23 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.72 to 4.67 (m, 1H), 4.43 (q, J = 11.7Hz, 2H), 3.80 (s, 3H), 3.78-3.77 (m, 2H), 3.72-3, 66 (m, 3H), 3.63 (s, 3H), 3.43-3.38 (m, 1H), 3.32-3.26 (m, 3H), 3.15 (s, 3H) , 2.72 (d, J = 9.0 Hz, 1H), 2.65 (brd, J = 8.7 Hz, 1H), 2.59-2.51 (m, 1H), 1.79- 1.72 (m, 1H), 1.32 (s, 3H), 1.06 (d, J = 6.6Hz, 3H), 0.89 (s, 9H), 0.87 (s, 9H ), 0.86 (s, 18H), 0.14 (s, 3H), 0.09 (s, 3H), 0.06 (s, 3H), 0.05 (s, 6H), 0.04 (s, 3H), 0.00 (s, 6H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 210.7, 172.1, 159.1, 130.3, 129.0, 113.7, 75.9, 72.6, 72.1, 68.1 , 63.7, 63.3, 61.4, 61.1, 60.1, 59.9, 57.6, 55.1, 37.2, 33.8, 29.7, 26.1, 26 , 0, 25.9, 25.8, 18.2, 18.1, 18.0, 15.2, 13.2, -4.3, -4.5, -4.7, -4.9 , -5.2, -5.3, -5.4, -5.5.
MS (ESI) m / z: 993 (M + 23) ⁺ .
[α] ²⁵ _D - 20.3 (c 0.50, CH ₂ Cl ₂ ).
R _f = 0.40 (Hex: EtOAc, 4: 1).

Example 41: Compound 16b

To a solution of 15b (725 mg, 0.745 mmol) in CH ₂ Cl ₂ (15 mL) was added Dess-Martin periodinane (1.26 g, 2.98 mmol) and a catalytic amount of NaHCO ₃ at 23 ° C. The reaction mixture was stirred at 23 ° C for 2 h. A saturated aqueous solution of NaHCO ₃ (30 mL) was added and the mixture extracted with CH ₂ Cl ₂ (3 x 40 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue (720 mg) was used without further purification in the next reaction.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.21 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 4.68 to 4.64 (m, 1H), 4.41 (q, J = 11.7Hz, 2H), 3.98-3.85 (m, 3H), 3.76 (s, 3H), 3.67 (dd, J = 9.9, 3.0Hz, 1H), 3.63 (s, 3H), 3.58 (d, J = 7.8Hz, 1H), 3.43 (dd, J = 9.3 , 6.9Hz, 1H), 3.30-3.23 (m, 2H), 3.11 (s, 3H), 3.93-2.88 (m, 1H), 2.62-2, 57 (m, 2H), 2.55 (d, J = 9.3Hz, 1H), 1.75-1.70 (m, 1H), 1.26 (s, 3H), 1.03 (i.e. , J = 6.6 Hz, 3H), 0.87 (s, 9H), 0.84 (s, 9H), 0.83 (s, 9H), 0.82 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H), 0.05 (s, 6H), 0.01 (s, 3H), 0.00 (s, 3H), -0.02 (s, 3H ), -0.03 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 208.4, 171.3, 159.4, 130.6, 129.3, 114.0, 76.0, 72.9, 66.9, 64.1 , 63.0, 61.4, 60.7, 60.6, 58.7, 58.5, 55.4, 34.1, 26.4, 26.3, 26.2, 26.1, 26 , 0, 18.5, 18.4, 18.3, 18.2, 15.5, 14.4, 13.0, -4.3, -4.4, -4.6, -4.7 , -4.9, -5.1, -5.2.
MS (ESI) m / z: 992 (M + 23) ⁺ .
[α] ²⁵ _D + 39.7 (c 0.5, CH ₂ Cl ₂ ).
R _f = 0.45 (Hex: EtOAc, 4: 1).

Example 42: Compound 17a

To a solution of 16a (289 mg, 0.3 mmol) in a mixture of CH ₂ Cl ₂ : H ₂ O (10: 0.5 mL) at 23 ° C was 2,3-dichloro-5,6-dicyano -1,4-benzoquinone (200 mg, 0.89 mmol) was added. The reaction mixture was stirred at 23 ° C for 45 min. A saturated aqueous solution of NaHCO ₃ (30 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (3 x 40 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in MeOH, NaBH ₄ (35 mg, 0.95 mmol) added and the reaction mixture was stirred at 23 ° C for 30 min. Then the reaction mixture was concentrated under reduced pressure. A saturated aqueous solution of NaHCO ₃ (20 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (3 x 30 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 6: 1) and Compound 17a (153 mg, 60%) was obtained as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 4.56 to 4.51 (m, 1H), 3.95 to 3.74 (m, 4H), 3.64 (s, 3H), 3.61 ( bs, 1H), 3.53 (d, J = 3.9Hz, 1H), 3.51-3.46 (m, 1H), 3.42-3.37 (m, 1H), 3.23 -3.18 (m, 1H), 3.14 (s, 3H), 2.69 (brd, J = 6.3 Hz, 1H), 2.65 (brd, J = 5.1 Hz, 1H) , 2.58 (d, J = 9.6 Hz, 1H), 1.72-1.64 (m, 1H), 1.32 (s, 3H), 0.95 (d, J = 6.9 Hz, 3H), 0.90 (s, 9H), 0.88 (s, 9H), 0.87 (s, 9H), 0.85 (s, 9H), 0.13 (s, 3H), 0.09 (s, 3H), 0.05 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H), 0.00 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 212.7, 171.9, 75.6, 67.6, 65.5, 64.2, 63.2, 61.4, 61.1, 60.9 , 60.6, 60.4, 38.1, 35.7, 32.1, 31.9, 29.7, 26.0, 25.9, 18.4, 18.3, 18.1, 18 , 0, 14.2, 14.2, -4.5, -4.6, -4.7, -5.2, -5.3, -5.4, -5.5.
MS (ESI) m / z: 872 (M + 23) ⁺ .
[α] ²⁵ _D - 29.5 (c 0.5, CH ₂ Cl ₂ ).
R _f = 0.20 (Hex: EtOAc, 4: 1).

Example 43: compound 17b

To a solution of the crude product 16b (0.745 mmol) in a mixture of CH ₂ Cl ₂ : H ₂ O (10: 0.5 mL) at 23 ° C 2,3-dichloro-5,6-dicyano-1,4 benzoquinone (507 mg, 2.23 mmol). The reaction mixture was stirred at 23 ° C for 40 min. A saturated aqueous solution of NaHCO ₃ (30 mL) was added and the mixture extracted with CH ₂ Cl ₂ (3 x 40 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in MeOH and NaBH ₄ (35 mg, 0.95 mmol) was added portionwise over 2 h at 23 ° C. Then, the reaction solution was concentrated under reduced pressure. A saturated aqueous solution of NaHCO ₃ (20 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (3 x 30 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hex: EtOAc, 6: 1) to give compound 17b (474 mg, 75% for two steps) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 4.58 (dt, J = 9.9, 3.0 Hz, 1H), 4.13 to 3.99 (m, 3H), 3.88 (td, J = 9.0, 2.4Hz, 2H), 3.64 (s, 3H), 3.60 (dd, J = 8.7, 4.0Hz, 1H), 3.54-3.45 (m, 1H), 3.43 (d, J = 3.6Hz, 1H), 3.24 (dt, J = 9.9, 3.0Hz, 1H), 3.15-3.13 ( m, 1H), 3.11 (s, 3H), 2.56-2.48 (m, 1H), 2.42 (d, J = 9.6Hz, 1H), 2.30 (dd, J = 16.2, 2.4 Hz, 1H), 1.27 (s, 3H), 0.93 (s, 9H), 0.91 (m, 3H), 0.88 (s, 9H), 0 , 86 (s, 18H), 0.15 (s, 3H), 0.14 (s, 3H), 0.12 (s, 3H), 0.07 (s, 6H), 0.04 (s, 6H), 0.01 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 213.0, 171.4, 74.6, 65.7, 65.5, 64.1, 63.6, 63.5, 62.3, 61.1 , 60.1, 59.1, 35.9, 34.8, 32.0, 29.6, 26.1, 26.0, 25.8, 25.7, 18.5, 18.3, 17 , 9, 14.2, 14.0, -4.5, -4.7, -5.0, -5.2, -5.3, -5.5, -5.6.
MS (ESI) m / z: 872 (M + 23) ⁺ .
[α] ²⁵ _D - 14.4 (c 0.5, CH ₂ Cl ₂ ).
R _f = 0.30 (Hex: EtOAc, 4: 1).

Example 44: Compound 17c

To a solution of 15b (289 mg, 0.3 mmol) in a mixture of CH ₂ Cl ₂ : H ₂ O (10: 0.5 mL) at 23 ° C was 2,3-dichloro-5,6-dicyano -1,4-benzoquinone (200 mg, 0.89 mmol) was added. The reaction mixture was stirred at 23 ° C for 30 min. A saturated aqueous solution of NaHCO ₃ (30 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (3 x 40 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was added min. MeOH, NaBH ₄ (35 mg, 0.95 mmol) and the reaction mixture was stirred at 23 ° C for 30 min. Then the reaction mixture was concentrated under reduced pressure. A saturated aqueous solution of NaHCO ₃ (20 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (3 x 30 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 7: 1) to give compound 17c (61 mg, 24%) as a white solid.
¹ H NMR (300 MHz, CDCl ₃₎ δ 4.70 to 4.66 (m, 1H), 4.05 to 4.03 (m, 2H), 3.85 to 3.81 (m, 3H), 3.68 (s, 3H), 3.67-3.65 (m, 1H), 3.50 (br t, J = 9.3Hz, 2H), 3.38 (d, J = 7.5 Hz, 1H), 3.18 (bs, 3H), 2.64 (d, J = 8.7 Hz, 1H), 2.50 (dd, J = 15.0, 1.8 Hz, 1H), 2.09-2.07 (m, 1H), 2.00-1.95 (m, 1H), 1.78-1.77 (m, 1H), 1.27 (s, 3H), 1, 09 (d, J = 6.9 Hz, 3H), 0.91 (s, 9H), 0.88 (s, 9H), 0.87 (s, 9H), 0.85 (s, 9H), 0.84 (s, 9H), 0.14 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.05 (s , 3H), 0.04 (s, 3H), 0.03 (s, 3H), -0.02 (s, 3H).
MS (ESI) m / z: 874 (M + 23) ⁺ .
R _f = 0.26 (Hex: EtOAc, 4: 1).

Example 45: Compound 18a

To a solution of 17a (113 mg, 0.13 mmol) in CH ₂ Cl ₂ (2 mL) was added Dess-Martin periodinane (141 mg, 1.33 mmol) and a catalytic amount of NaHCO ₃ at 23 ° C. The reaction mixture was stirred at 23 ° C for 40 min. A saturated aqueous reading of NaHCO3 (10 mL) was added and the mixture extracted with CH ₂ Cl ₂ (3 x 10 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the corresponding aldehyde (R _f = 0.33 Hex: EtOAc 4: 1). In the meantime, potassium tert -butoxide (0.85 mL) was added at 0 ° C to a suspension of triphenylphosphonium bromide (395 mg) in toluene (7 mL) 1 M / THF. An orange solution resulted, which was stirred at 0 ° C for 25 min and then cooled to -78 ° C. Subsequently, a solution of the fresh aldehyde crude product in toluene (5 mL) was added dropwise to the previous suspension at -78 ° C and the mixture was then brought to 23 ° C within 14 h. The reaction mixture was diluted with CH ₂ Cl ₂ (10 mL) and washed with a saturated NaHCO ₃ solution (15 mL). The organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 15: 1) to give compound 18a (80 mg, 70% for two steps) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 5.52 to 5.41 (m, 1H), 5.26 (td, J = 10.2, 1.5 Hz, 1H), 4.73 to 4, 68 (m, 1H), 3.81 (dd, J = 10.5, 4.5 Hz, 1H), 3.75-3.69 (m, 2H), 3.63 (s, 3H), 3 , 60 (s, 2H), 3.29-3.24 (m, 1H), 3.22-3.16 (m, 1H), 3.14 (s, 3H), 2.71 (d, J = 9.3 Hz, 1H), 2.65 (brd, J = 7.2 Hz, 1H), 2.52 (dd, J = 15.9, 3.3 Hz, 1H), 2.44-2 , 35 (m, 1H), 1.61 (dd, J = 6.9, 1.5 Hz, 3H), 1.29 (s, 3H), 1.10 (d, J = 6.3 Hz, 3H), 0.89 (s, 9H), 0.88 (s, 9H), 0.87 (s, 9H), 0.86 (s, 9H), 0.14 (s, 3H), 0, 10 (s, 3H), 0.06 (s, 3H), 0.05 (s, 6H), 0.04 (s, 3H), 0.01 (s, 3H), 0.00 (s, 3H ).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 2H, 2, 172.2, 130.9, 124.2, 76.7, 67.7, 64.9, 62.8, 62.2, 61.1 , 60.7, 59.5, 57.3, 37.7, 31.8, 29.7, 26.2, 26.0, 25.9, 25.8, 18.9, 18.3, 18 , 2, 18,1, 18,1, 13,1, 12,3, -4,3, -4,4, -4,7, -4,9, -5,3, -5,4, - 5.5.
MS (ESI) m / z: 882 (M + 23) ⁺ .
R _f = 0.52 (Hex: EtOAc, 4: 1).

Example 46: compound 18b

To a solution of 17b (474 mg, 0.557 mmol) in CH ₂ Cl ₂ (10 mL) was added Dess-Martin periodinane (590 mg, 1.39 mmol) and a catalytic amount of NaHCO ₃ at 23 ° C. The reaction mixture was stirred at 23 ° C for 40 min. A saturated aqueous solution of NaHCO ₃ (30 mL) was added and the mixture extracted with CH ₂ Cl ₂ (3 x 40 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure, whereupon the corresponding aldehyde is obtained (R _f = 0.38 Hex: EtOAc 4: 1). In the meantime, potassium tert -butoxide (3.56 mL) was added at 0 ° C to a suspension of triphenylphosphonium bromide (1.64 g) in toluene (15 mL) 1 M / THF. An orange solution was obtained which was stirred at 0 ° C for 25 min and then cooled to -78 ° C. Subsequently, a solution of the fresh aldehyde crude product in toluene (10 mL) was added dropwise to the previous suspension at -78 ° C and the mixture was then brought to 23 ° C within 14 h. The reaction mixture was diluted with CH ₂ Cl ₂ (10 mL) and washed with a saturated NaHCO ₃ solution (30 mL). The organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (hex: EtOAc, from 15: 1 to 10: 1) to give the mixture Compound 18b (347 mg, 72% for 2 steps) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 5.51 to 5.45 (m, 1H), 5.29 (td, J = 11.1, 1.5 Hz, 1H), 4.76 to 4, 71 (m, 1H), 3.98 (dd, J = 9.6, 3.3 Hz, 1H), 3.90 (dd, J = 9.6, 7.2 Hz, 1H), 3.69 3.68 (m, 2H), 3.65 (s, 3H), 3.59 (d, J = 8.7 Hz, 1H), 3.36-3.30 (m, 1H), 3, 15 (s, 3H), 2.92-2.88 (m, 1H), 2.62 (d, J = 9.3Hz, 1H), 2.58 (d, J = 2.1Hz, 1H ), 2.55-2.52 (m, 1H), 2.43-2.35 (m, 1H), 1.61 (dd, J = 6.6, 1.5 Hz, 3H), 1, 26 (s, 3H), 1.10 (d, J = 6.6 Hz, 3H), 0.92 (s, 9H), 0.86 (s, 9H), 0.85 (s, 9H), 0.84 (s, 9H), 0.12 (s, 3H), 0.09 (s, 9H), 0.03 (s, 3H), 0.00 (s, 9H).
¹³ C NMR (75 MHz, _CDCl3) δ 208.63, 172.3, 130.9, 124.2, 76.2, 66.7, 65.0, 62.5, 61.3, 61.1 , 60.0, 56.8, 36.7, 31.8, 29.7, 26.2, 25.9, 25.9, 18.9, 18.3, 18.2, 18.1, 18 , 0, 13.1, 12.0, -4.5, -4.7, -4.8, -4.9, -5.2, -5.3, -5.5.
MS (ESI) m / z: 882 (M + 23) ⁺ .
[α] ²⁵ _D + 73.9 (c 0.5, CH ₂ Cl ₂ ).
R _f = 0.50 (Hex: EtOAc, 4: 1).

Example 47: Compound 18c

Following the procedure described in Example 45, 17c (60 mg, 0.07 mmol) after purification of the crude product by flash column chromatography (Hex: EtOAc, 10: 1) was converted to 18c (30 mg, 50%, pale yellow oil).
¹ H NMR (300 MHz, CDCl ₃₎ δ 5.48 to 5.40 (m, 1H), 5.32 to 5.25 (m, 1H), 4.85 to 4.80 (m, 1H), 4.10 (dd, J = 11.1, 2.4 Hz, 1H), 4.01 (brt, J = 9.0 Hz, 1H), 3.83 (dd, J = 10.2, 5, 4 Hz, 1H), 3.76 (br d, J = 10.8 Hz, 1H), 3.66 (s, 3H), 3.62 (d, J = 10.2 Hz, 1H), 3, 52 (dd, J = 10.2 6.0 Hz, 1H), 3.37 (d, J = 8.4 Hz, 1H), 3.16 (s, 3H), 2.71 (d, J = 9.3Hz, 1H), 2.61-2.58 (m, 1H), 2.50-2.39 (m, 2H), 2.03-2.00 (m, 1H), 1.77 (Br d, J = 8.4 Hz, 1H), 1.59 (dd, J = 6.6, 1.5 Hz, 3H), 1.24 (s, 3H), 1.13 (d, J = 6.9 Hz, 3H), 0.91 (s, 9H), 0.90 (s, 9H), 0.86 (s, 9H), 0.85 (s, 9H), 0.15 (s , 3H), 0.13 (s, 3H), 0.10 (s, 6H), 0.08 (s, 3H), 0.03 (s, 3H), 0.01 (s, 3H).
MS (ESI) m / z: 862 (M + 1) ⁺ .
R _f = 0.48 (Hex: EtOAc, 4: 1).

Example 48: Compound 19a

To a solution of 18a (80 mg, 0.093 mmol) in THF (1.5 mL) at 23 ° C was added BrMgEt (0.28 mL, 1.0 M in THF, 0.28 mmol). The reaction mixture was stirred at 23 ° C for 3 h. A saturated aqueous solution of NaHCO ₃ (10 mL) was added and the mixture extracted with CH ₂ Cl ₂ (3 x 15 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 30: 1) to give compound 19a (57 mg, 75%) as a white solid.
¹ H NMR (300 MHz, CDCl ₃₎ δ 5.53 to 5.43 (m, 1H), 5.26 (td, J = 10.2, 1.5 Hz, 1H), 4.71 to 4, 66 (m, 1H), 3.77 (dd, J = 10.8, 4.5 Hz, 1H), 3.67 (d, J = 5.7 Hz, 2H), 3.60 (t, J = 9.3Hz, 1H), 3.50 (d, J = 8.7Hz, 1H), 3.34-3.27 (m, 1H), 3.20-3.14 (m, 1H) , 2.64 (d, J = 9Hz, 1H), 2.58-2.56 (m, 2H), 2.41-2.34 (m, 3H), 1.61 (dd, J = 6 , 6, 1.8 Hz, 3H), 1.29 (s, 3H), 1.10 (d, J = 6.3 Hz, 3H), 1.00 (t, J = 7.5 Hz, 3H ), 0.89 (s, 18H), 0.87 (s, 9H), 0.86 (s, 9H), 0.15 (s, 3H), 0.10 (s, 3H), 0.05 (s, 3H), 0.04 (s, 6H), 0.03 (s, 6H), 0.00 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 2H, 9, 209.2, 130.9, 124.4, 77.3, 67.4, 65.0, 62.7, 62.1, 60.8 , 59.8, 57.6, 47.2, 37.1, 31.7, 29.7, 26.3, 26.0, 25.9, 25.8, 18.9, 18.4, 18 , 3, 18.1, 18.0, 13.1, 12.2, 7.5, -4.2, -4.3, -4.7, -5.0, -5.3, -5 , 5, -5,6.
MS (ESI) m / z: 851 (M + 23) ⁺ .
[α] ²⁵ _D - 11.3 (c 0.5, CH ₂ Cl ₂ ).
R _f = 0.74 (Hex: EtOAc, 4: 1).

Example 49: Compound 19b

To a solution of 18b (347 mg, 0.4 mmol) in THF (4 mL) at 23 ° C was added 1 M / THF BrMgEt (1.5 mL, 1.5 mmol). The reaction mixture was stirred at 23 ° C for 3 h. A saturated aqueous solution of NaHCO ₃ (30 mL) was added and the mixture extracted with CH ₂ Cl ₂ (3 x 30 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 40: 1) to give 19c (280 mg, 84%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 5.54 to 5.44 (m, 1H), 5.30 (td, J = 10.2, 1.5 Hz, 1H), 4.71 to 4, 67 (m, 1H), 3.95 (dd, J = 9.6, 3.3 Hz, 1H), 3.91-3.85 (m, 1H), 3.69 (d, J = 1, 5Hz, 1H), 3.67 (s, 3H), 3.57 (d, J = 9.0Hz, 1H), 3.34-3.27 (m, 1H), 2.89-2, 84 (m, 1H), 2.62-2.58 (m, 1H), 2.60 (d, J = 9.3Hz, 1H), 2.44-2.30 (m, 4H), 1 , 61 (dd, J = 6.9, 1.5 Hz, 3H), 1.25 (s, 3H), 1.11 (d, J = 6.6 Hz, 3H), 1.02 (t, J = 7.5Hz, 3H), 0.90 (s, 9H), 0.86 (s, 9H), 0.85 (s, 9H), 0.82 (s, 9H), 0.13 ( s, 3H), 0.10 (s, 3H), 0.09 (s, 6H), 0.01 (s, 3H), 0.00 (s, 9H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 209.0, 208.7, 130.9, 124.1, 76.0, 65.8, 64.9, 62.3, 61.3, 58.0 , 57.2, 46.7, 36.7, 31.8, 26.2, 25.9, 25.8, 18.8, 18.3, 18.2, 18.1, 18.0, 13 , 1, 12.1, 7.5, -4.5, -4.6, -4.8, -4.9, -5.3, -5.4, -5.5.
MS (ESI) m / z: 851 (M + 23) ⁺ .
[α] ²⁵ _D + 69.5 (c 0.5, CH ₂ Cl ₂ ),
R _f = 0.76 (Hex: EtOAc, 4: 1).

Example 50: Compounds 20a and 20c

To a solution of 19a (160 mg, 0.19 mmol) in THF (6 mL) was added at 23 ° C simultaneously TRAF (1.52 mL, 1.0 M in THF, 1.52 mmol) and AcOH (77 μL , 1.35 mmol) was added. The reaction mixture was stirred at 23 ° C for 16 h. H ₂ O (10 mL) was added and the mixture was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hex: EtOAc, from 4: 1 to 1: 1) to give a tautomeric equilibrium of 20a and 20c (77 mg, 82%) as a white solid.
¹ H NMR (500 MHz, CDCl ₃ ) (main product data) δ 5.54-5.49 (m, 1H), 5.24 (m, 1H), 4.79 (d, J = 2.5 Hz , 1H), 4.30 (dd, J = 12.0 Hz, 1H), 3.84 (dd, J = 12.5, 4.0 Hz, 1H), 3.67-3.66 (m, 2H), 3.33 (d, J = 10.0 Hz, 1H), 3.30-3.26 (m, 1H), 2.77 (ddd, J = 11.5, 5.0, 2, 5Hz, 1H), 2.51 (d, J = 8.5Hz, 1H), 2.45-2.39 (m, 1H), 2.02 (dd, J = 14.0, 3.5 Hz, 1H), 1.73 (dd, J = 14.0, 3.0 Hz, 1H), 1.63 (dd, J = 7.0, 1.5 Hz, 3H), 1.61-1 , 58 (m, 2H), 1.31 (s, 3H), 1.12 (d, J = 6.5 Hz, 3H), 0.93 (t, J = 7.5 Hz, 3H), 0 , 86 (s, 9H), 0.11 (s, 3H), -0.04 (s, 3H).
¹³ C NMR (125 MHz, CDCl ₃ ) (main product data) δ 213.1, 130.5, 124.8, 97.3, 78.6, 65.3, 65.2, 62.2, 61, 3, 55.5, 55.2, 54.7, 37.3, 34.5, 31.6, 29.7, 26.0, 18.7, 13.3, 11.4, 7.4, -4.4, -5.2.
MS (ESI) m / z: 509 (M + 23) ⁺ , 451 (M + H-2 × H ₂ O) ⁺ .
R _f 0.56 (Hex: EtOAc, 1: 2).

Example 51: Compounds 20b and 20d

According to the procedure described in Example 50, 19b (35 mg, 0.04 mmol) was converted to a tautomeric equilibrium of 20b and 20d by purification of the crude product by flash column chromatography (Hex: EtOAc, from 4: 1 to 1: 1) (12 mg, 60%, pale yellow oil.
¹ H NMR (500 MHz, CDCl ₃ ) (major product data) δ 5.56-5.50 (m, 1H), 5.32-5.26 (m, 1H), 4.38 (ddd, J = 15.5, 11.5, 5.0 Hz, 1H), 3.86-3.76 (m, 4H), 3.53 (d, J = 9.5 Hz, 1H), 3.24-3 , 20 (m, 1H), 2.89 (ddd, J = 14.5, 11.0, 4.5 Hz, 1H), 2.59 (d, J = 9.5 Hz, 1H), 2, 46-2.41 (m, 1H), 2.08 (dd, J = 12.5, 5.0 Hz, 1H), 1.69-1.66 (m, 2H), 1.64 (dd, J = 7.0, 2.0 Hz, 3H), 1.46 (dd, J = 13.0, 12.0 Hz, 1H), 1.30 (s, 3H), 1.13 (d, J = 7.0 Hz, 3H), 0.97 (t, J = 7.5 Hz, 3H), 0.86 (s, 3H), 0.14 (s, 3H), 0.00 (s, 3H ).
¹³ C NMR (125 MHz, CDCl ₃ ) (main product data) δ 213.1, 130.6, 124.7, 98.8, 77.0, 66.8, 65.1, 62.2, 60, 8, 60.0, 59.0, 40.1, 35.5, 31.5, 29.7, 26.1, 18.8, 18.2, 13.3, 11.5, 7.4, -4,3, -5,0.
MS (ESI) m / z: 509 (M + 23) ⁺ , 451 (M + H-2 × H ₂ O) ⁺ .
[α] ²⁵ _D + 55.0 (c 0.5, CH ₂ Cl ₂ ).
R _f = 0.51 (Hex: EtOAc, 1: 2).

Example 52: Compounds 3a and 4a

To a solution of 19a (238 mg, 0.29 mmol) in DMF (5 mL) was added at 23 ° C simultaneously TRAF (2.9 mL, 1.0 M in THF, 2.9 mmol) and AcOH (116 μL , 2 mmol) was added. The reaction mixture was stirred at 23 ° C for 7 h. A saturated aqueous solution of NaHCO ₃ (10 mL) was added and the mixture was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hex: EtOAc, from 4: 1 to 0: 1) to give a tautomeric equilibrium of 3a and 4a (25 mg, 23%) as a colorless oil.
¹ H NMR (500 MHz, CD ₃ OD) (major product data) δ 5.56-5.51 (m, 1H), 5.31-5.26 (m, 1H), 4.75 (m, 1H ), 4.29 (dd, J = 11.5, 11.5 Hz, 1H), 3.72 (dd, J = 12.5, 4.0 Hz, 1H), 3.67-3.62 ( m, 2H), 3.29-3.27 (m, 1H), 3.16 (d, J = 10.0 Hz, 1H), 2.89 (ddd, J = 11.5, 4.5, 2.0 Hz, 1H), 2.59 (d, J = 9.5 Hz, 1H), 1.93 (dd, J = 14.0, 3.0 Hz, 1H), 1.75 (dd, J = 14.5, 3.0 Hz, 1H), 1.65 (dd, J = 6.5, 2.0 Hz, 3H), 1.56 (q, J = 7.5 Hz, 2H), 1.34 (s, 3H), 1.09 (d, J = 7.0 Hz, 3H), 0.92 (t, J = 7 5 Hz, 3H). ¹ H NMR (500 MHz, CDCl ₃ ) (major product data) δ 5.55-5.48 (m, 1H), 5.27-5.20 (m, 1H), 4.74 (brd, J = 2.0 Hz, 1H), 4.32 (dd, J = 13.0, 13.0 Hz, 1H), 3.89 (dd, J = 12.5, 4.0 Hz, 1H), 3, 76 (dd, J = 10.0, 9.0 Hz, 1H), 3.63 (dd, J = 10.5, 3.5 Hz, 1H), 3.33 (d, J = 9.5 Hz , 1H), 3.29 (dd, J = 9.5, 4.0 Hz, 1H), 2.94 (ddd, J = 11.5, 5.0, 2.5 Hz, 1H), 2, 68 (d, J = 9.0 Hz, 1H), 2.44-2.39 (m, 1H), 2.02 (dd, J = 14.0, 3.0 Hz, 1H), 1.73 (dd, J = 14.0, 3.0 Hz, 1H), 1.62 (dd, J = 7.0, 1.5 Hz, 3H), 1.59-1.56 (m, 2H), 1.33 (s, 3H), 1.11 (d, J = 6.0Hz, 3H), 0.94 (t, J = 7.5Hz, 3H).
¹³ C NMR (125 MHz, CDCl ₃ ) (main product data) δ 214.2, 130.0, 125.0, 97.3, 77.2, 66.8, 66.7, 65.2, 63, 0, 55.6, 54.6, 52.9, 37.1, 34.5, 31.3, 18.6, 13.3, 11.6, 7.4.
MS (ESI) m / z: 767 (2xM + 23) ⁺ , 395 (M + 23) ⁺ , 377 (M + 23-H ₂ O) ⁺ .
R _f 0.24 (Hex: EtOAc, 1: 2).

Example 53: Compounds 3b and 4b

Following the procedure described in Example 52, 19b (200 mg, 0.24 mmol) was purified by flash column chromatography (Hex: EtOAc, from 4: 1 to 0: 1) to give tautomeric equilibrium of 3b and 4b (20 mg , 21%).
¹ H NMR (500 MHz, CDCl ₃ ) (main product data) δ 5.56-5.48 (m, 1H), 5.28-5.22 (m, 1H), 4.41-4.37 ( m, 1H), 3.97-3.73 (m, 5H), 3.34-3.22 (m, 1H), 2.98 (ddd, J = 4.5 Hz, 11.5 Hz, 14 , 5 Hz, 1H), 2.73 (d, J = 9 Hz, 1H), 2.46-2.42 (m, 1H), 2.09 (dd, J = 5 Hz, 13 Hz, 1H) , 1.67 (q, J = 7Hz, 2H), 1.63 (dd, J = 1.5Hz, 7Hz, 3H), 1.48-1.42 (m, 1H), 1.35 (s, 3H), 1.11 (dJ = 7Hz, 3H), 0.96 (t, J = 7Hz, 3H).
MS (ESI) m / z: 395 (M + 23) ^+, 767 (2M + 23) ^+, 377 (M + 23-H ₂ O) ^+, 337 (M + 1-2H ₂ O) ^+, 319 ( M + 1-3H ₂ O) ⁺ . HRMS (TOF) Ber. for C ₁₉ H ₃₂ O ₇ Na: 395.2046. found 395,2019.
R _f 0.15 (Hex: EtOAc, 1: 2).

Example 54: Connection 21

Compound 21 was prepared according to the method described in DA Evans et al., J. Am. Chem. Soc. 1984, 106, 4261-4263.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.21 (m, 1H), 7.12 (m, 1H), 4.44 (m, 1H), 4.20 (m, 2H), 2.36 (m, 1H), 1.91 (dd, J = 6.6, 1.2Hz, 3H), 0.88 (d, J = 6.9Hz, 3H), 0.83 (d, J = 6.9 Hz, 3H).

Example 55: compound 22

To a solution of 21 (9.39 g, 0.047 mol) in CH ₂ Cl ₂ (75 mL) at -78 ° C was Bu ₂ BOTf (52.4 mL, 1.0 M in CH ₂ Cl ₂ , 52, 4 mmol) and Et ₃ N (9.3 mL, 0.067 mol). The reaction mixture was stirred at -78 ° C for 1 h, cooled at 0 ° C for 15 min and again at -78 ° C. This solution was added at -50 ° C over a solution of 8a (9 g, 0.016 mol) in CH ₂ Cl ₂ (25 mL) and the mixture was stirred at -50 ° C for an additional 10 days. A saturated aqueous solution of NH ₄ Cl (150 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (2 x 100 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hex: EtOAc, from 15: 1 to 2: 1) to give compound 22 alone in about 15%, along with another diastereoisomer (12 g, 80%) as one colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.20 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.20 (dt, J = 17.4, 10.2 Hz, 1H), 5.25 (dd, J = 11.1, 0.6 Hz, 1H), 5.20 (dd, J = 19.2, 0.6 Hz, 1H), 4.47-4.33 (m, 3H), 4.28-4.09 (m, 3H), 3.95 (br d, J = 3.6Hz, 1H), 3.80 ( s, 3H), 3.65-3.56 (m, 2H), 3.33 (br d, J = 7.2 Hz, 2H), 2.90 (d, J = 9.3 Hz, 1H) , 2.45-2.35 (m, 1H), 2.33-2.23 (q, J = 6.9Hz, 1H), 1.83-1.73 (m, 1H), 1.56 -1.46 (m, 1H), 1.28 (s, 3H), 1.03 (d, J = 6.9 Hz, 3H), 0.90 (s, 9H), 0.87 (s, J = 6.9 Hz, 3H), 0.83 (s, J = 6.9 Hz, 3H), 0.82 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 172.9, 158.7, 153.0, 132.1, 128.7, 128.3, 118.8, 113.3, 77.0, 74.6 , 72.3, 69.0, 64.7, 64.5, 63.0, 62.9, 62.7, 60.0, 58.5, 58.1, 58.0, 54.7, 50 , 4, 47.1, 32.9, 32.2, 30.9, 28.1, 27.9, 27.3, 25.6, 25.5, 17.8, 17.6, 14.3 , 14.3, 14.2, 14.1, -5.1, -5.3, -5.8, -5.9.
MS (ESI) m / z: 786 (M + 23) ⁺ , 764 (M + H) ⁺ .
R _f = 0.32 (Hex: EtOAc, 4: 1).

Example 56: compound 23

To a solution of the diastereomeric mixture (5: 1) of 22 (3.9 g, 5.1 mmol) in THF: H ₂ O (5: 1, 75 mL) was added LiBH ₄ (13 mL, 2 , 0M in THF, 26mmol). The reaction mixture was stirred at 0 ° C for 30 minutes and at 23 ° C for 2.5 hours. A saturated aqueous solution of NH ₄ Cl (100 mL) was added and the mixture extracted with EtOAc (3 x 150 mL). The combined organic phases were dried but Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue 23 (3.4 g) was used in the next step without further purification.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.17 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 9.0 Hz, 2H), 6.17 to 6.05 (m, 1H), 5.20 (dd, J = 10.5, 1.8 Hz, 1H), 5.13 (dd, J = 17.7, 1.8 Hz, 1H), 4.40- 4.35 (m, 2H), 4.02 (d, J = 9.6Hz, 1H), 3.85-3.73 (m, 2H), 3.80 (s, 3H), 3.48 -3.47 (m, 2H), 3.39-3.34 (m, 1H), 3.30-3.24 (m, 1H), 2.66 (d, J = 9.3 Hz, 1H , 2.31-2.28 (m, 1H), 1.81-1.74 (m, 2H), 1.28 (s, 3H), 1.05 (d, J = 6.6 Hz, 3H), 0.92 (s, 9H), 0.86 (s, 9H), 0.17 (s, 3H), 0.12 (s, 3H), 0.00 (s, 3H), -0 , 01 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 159.4, 135.8, 130.3, 129.2, 118.3, 114.0, 79.1, 73.2, 73.0, 72.3 , 67.2, 65.6, 64.4, 60.4, 55.4, 47.7, 46.7, 33.6, 26.2, 18.5, 18.2, 15.0, 12 , 9, -4, 1, -5, -5, -5, 4.
MS (ESI) m / z: 661 (M + 23) ⁺ , 639 (M + H) ⁺
R _f = 0.18 (Hex: EtOAc, 4: 1).

Example 57: Connection 24

To a solution of crude product 23 (5 mmol) in CH ₂ Cl ₂ (60 mL) at 23 ° C was added imidazole (1.02 g, 15 mmol) and TBSCl (1.13 g, 7.5 mmol). The reaction mixture was stirred at 23 ° C for 15 min. Then, a saturated aqueous solution of NH ₄ Cl (70 mL) was added and the reaction extracted with CH ₂ Cl ₂ (2 x 100 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 20: 1) to give compound 24 (1.7 g, 43% for two steps) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.19 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.96 to 5.84 (m, 1H), 5.12-5.05 (m, 2H), 4.37 (q, J = 11.4Hz, 2H), 4.0 (d, J = 9.3Hz, 1H) , 3.92 (s, 1H), 3.86-3.77 (m, 2H), 3.80 (s, 3H), 3.57-3.46 (m, 3H), 3.37-3 , 29 (m, 2H), 2.67 (d, J = 9.3 Hz, 1H), 2.42-2.36 (m, 1H), 1.83-1.76 (m, 2H), 1.30 (s, 3H), 1.06 (d, J = 6.9Hz, 3H), 0.93 (s, 9H), 0.88 (s, 9H), 0.87 (s, 9H ), 0.17 (s, 3H), 0.12 (s, 3H), 0.03 (s, 9H), 0.00 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 159.4, 136.0, 130.4, 129.2, 118.0, 114.0, 79.2, 73.1, 72.9, 68.2 , 65.3, 64.7, 64.6, 60.7, 55.4, 49.1, 47.1, 33.6, 26.3, 26.2, 26.1, 18.5, 15 , 1, 12.9, -4.1, -4.9, -5.1, -5.2, -5.3.
MS (ESI) m / z: 775 (M + 23) ⁺ , 753 (M + H) ⁺
[α] ²⁵ _D -8.0 (c 0.50, CH ₂ Cl ₂ ).
R _f = 0.65 (Hex: EtOAc, 4: 1).

Example 58: Compound 25a

Via a solution of 24 (1.58 g, 2.09 mmol) in CH ₂ Cl ₂ (40 mL) was passed for 2 min at -78 ° C, an O ₃ stream. Then, Ph ₃ P (1.65 g, 6.27 mmol) was added and the mixture was warmed to room temperature and stirred for 1.5 h. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 20: 1) to give compound 25a (1.34 g, 85%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 9.77 (d, J = 3.0 Hz, 1H), 7.21 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 4.39 (s, 2H), 4.18 (dd, J = 9.9, 7.8 Hz, 1H), 4.08 (m, 1H), 4.04 -4.03 (m, 1H), 3.90 (dd, J = 9.9, 6.0 Hz, 1H), 3.81 (s, 3H), 3.73-3.68 (m, 2H ), 3.55-3.50 (dd, J = 10.5, 3.3 Hz, 1H), 3.40-3.27 (m, 2H), 2.67 (d, J = 9.3 Hz, 1H), 2.62 (m, 1H), 1.98-1.92 (m, 1H), 1.83-1.74 (m, 1H), 1.27 (s, 3H), 1 , 05 (d, J = 6.9 Hz, 3H), 0.92 (s, 9H), 0.86 (s, 9H), 0.85 (s, 9H), 0.17 (s, 3H) , 0.11 (s, 3H), 0.05 (s, 6H), 0.02 (s, 3H), 0.00 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 205.6, 159.4, 130.3, 129.4, 114.1, 79.2, 73.2, 72.9, 70.4, 65.5 , 64.0, 61.7, 60.9, 55.8, 55.4, 47.4, 33.6, 26.2, 26.0, 18.4, 18.2, 15.0, 12 , 9, -4, 1, -5, 5, -5, 2, -5, 3, -5, 5, -5, 4.
MS (ESI) m / z: 777 (M + 23) ⁺ .
[α] ²⁵ _D -7.9 (c 0.52, CH ₂ Cl ₂ ).
R _f = 0.67 (Hex: EtOAc, 4: 1).

Example 59: Compound 25b

To a solution of 25a (1.34 mg, 1.78 mmol) in CH ₂ Cl ₂ (50 mL) at 23 ° C was Dess-Martin Perio dinane (1.5 mg, 3.56 mmol) and a catalytic amount of NaHCO ₃ . The reaction mixture was stirred at 23 ° C for 50 min. A saturated aqueous solution of NaHCO 3 (60 mL) was added and the mixture extracted with CH ₂ Cl ₂ (3 x 70 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the aldehyde 25b, which was used in the following step without further purification.
¹ H NMR (300 MHz, CDCl _3): δ 9.59 (d, J = 2.7 Hz, 1H), 7.23 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6Hz, 2H), 4.36-4.48 (m, 2H), 4.22-4.29 (m, 1H), 3.98-4.07 (m, 1H), 3 , 81-3.88 (m, 1H), 3.80 (s, 3H), 3.64-3.78 (m, 2H), 3.32-3.45 (m, 4H), 2.47 (d, J = 9.3Hz, 1H), 1.68-1.81 (m, 1H), 1.24 (s, 3H), 1.03 (d, J = 6.7Hz, 3H) , 0.92 (s, 9H), 0.91 (s, 9H), 0.90 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H), 0.03 ( s, 3H), 0.02 (s, 3H), -0.01 (s, 3H), -0.02 (s, 3H).
R _f = 0.69 (Hex: EtOAc, 4: 1).

Example 60: Compounds 26a and 26b

To a solution of N-methoxy-N-methylacetamide (70 μL, 0.65 mmol) in THF (2 mL) at -78 ° C was added bis (trimethylsilyl) lithium amide (0.65 mL, 1.0 M in THF, 0.65 mmol) was added and the reaction mixture was stirred for 1 h at this temperature. Subsequently, a solution of 25a (165 mg, 0.22 mmol) in THF (4 mL) was added via the previous solution and the reaction mixture was stirred for a further 1 h at -78 ° C. Thereafter, a saturated aqueous solution of NH ₄ Cl (30 mL) was added and the reaction mixture extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hex: EtOAc, from 4: 1 to 1: 1) to give compounds 26a and 14b (1: 2) as colorless oils (139 mg, in an overall yield of 74%). ).
¹ H NMR (300 MHz, CDCl ₃ ) mixture of diastereomers δ 7.19-7.25 (m, 2H), 6.82-6.89 (m, 2H), 4.58-4.63 (m, 1H), 4.36-4.55 (m, 2H), 4.01-4.08 (m, 1H), 5.75-5.98 (m, 3H), 3.80 (s, 1, 98H), 3.79 (s, 1 02H), 3.65 (s, 1.98H), 3.64 (s, 1.02H), 3.44-3.65 (m, 2H), 3, 25-3.32 (m, 2H), 3.17 (s, 1.02H), 3.16 (s, 1.98H), 2.80-2.88 (m, 1H), 2.69 ( d, J = 9.3Hz, 0.66H), 2.68 (d, J = 9.0Hz, 0.34H), 2.65-2.74 (m, 1H), 2.00-2 , 09 (m, 1H), 1.74-1.88 (m, 2H), 1.69 (brs, 1H), 1.34 (s, 1.02H), 1.25 (s, 1, 98H), 1.07 (m, 3H), 0.92 (s, 5.94H), 0.90 (s, 3.06H), 0.89 (s, 3.06H), 0.88 (s , 5.94H), 0.85 (s, 3.06H), 0.83 (s, 5.94H), -0.02-0.18 (m, 18H).
MS (ESI) m / z: 880 (M + 23) ⁺ , 858 (M + 1) ⁺ .
R _f = 0.09 (Hex: EtOAc, 4: 1).

Example 61: Compounds 26c and 26d

To a solution of N-methoxy-N-methylacetamide (568 μL g, 5.34 mmol) in THF (15 mL) at -78 ° C was added bis (trimethylsilyl) lithium amide (1.0 M in THF) (5.34 g) mL, 5.34 mmol) and the reaction mixture was stirred for 1 h at this temperature. Subsequently, a solution of the crude product 25b (1.78 mmol) in THF (25 mL) was added via the previous solution and the reaction mixture was stirred at -78 ° C. for a further 3 h. Thereafter, a saturated aqueous solution of NH ₄ Cl (50 mL) was added and the reaction extracted with EtOAc (3 x 60 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hex: EtOAc, from 4: 1 to 2: 1) to give compounds 26c and 26d 1: 1.9) as colorless oils (910 mg, 60% overall yield) % for two levels).
¹ H NMR (300 MHz, CDCl ₃ ) mixture of diastereoisomers δ 7.25 (d, J = 8.7 Hz, 4H), 6.88 (d, J = 8.4 Hz, 4H), 4.64- 4.60 (m, 1H), 4.48-4.36 (m, 6H), 4.10-3.82 (m, 6H), 3.80 (s, 6H), 3.76-3, 71 (m, 2H), 3.66 (s, 6H), 3.61 (d, J = 3.3Hz, 1H), 3.53-3.48 (m, 2H), 3.44-3 , 29 (m, 6H), 3.18 (s, 6H), 3.01-2.80 (m, 3H), 2.61 (m, 1H), 2.57 (d, J = 9.0 Hz, 1H), 2.53 (d, J = 9.0 Hz, 1H), 1.81-1.67 (m, 2H), 1.32 (s, 3H), 1.31 (s, 3H ), 1.05 (d, J = 6.9 Hz, 6H), 0.89 (s, 18H), 0.87 (s, 9H), 0.86 (s, 9H), 0.85 (s , 9H), 0.84 (s, 9H), 0.1 (s, 6H), 0.07 (s, 9H), 0.06 (s, 3H), 0.02 (s, 3H), 0.01 (s, 6H), 0.00 (s, 3H), -0.01 (s, 3H), -0.01 (s, 3H). ¹³ C NMR (75 MHz, CDCl ₃₎ δ 211.0, 172.4, 159.0, 130.1, 128.9, 113.6, 77.0, 72.6, 72.0, 71.9 , 67.4, 66.1, 64.1, 64.0, 63.1, 63.0, 61.0, 60.8, 60.5, 60.1, 59.8, 58.9, 56 , 7, 55.1, 36.3, 33.5, 26.0, 25.7, 18.2, 18.0, 15.0, 12.5, -4.6, -4.7, - 5.0, -5.1, -5.5, -5.6.
MS (ESI) m / z: 878 (M + 23) ⁺ .
R _f = 0.44 (Hex: EtOAc, 2: 1). Similarly, R _f = 0.16 (Hex: EtOAc, 4: 1).

Example 62: Compounds 27a and 27b

To a solution of 26a and 26b (139 mg, 0.16 mmol) in CH ₂ Cl ₂ (8 mL) at 0 ° C was added 2,6-lutidine (57 μL, 0.49 mmol) and TBSOTf (56 μL, 0.24 mmol). The reaction mixture was stirred at 0 ° C for 30 min. Then a saturated aqueous solution of NH ₄ Cl (30 mL) was added and the reaction mixture extracted with CH ₂ Cl ₂ (2 x 25 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 10: 1) to give compound 27a (white solid) and 27b (colorless oil) (1: 2) (113 mg, in an overall yield of 72%). ,
27a: ¹ H NMR (300 MHz, CDCl ₃₎ δ 7.28 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.66 (brd , J = 9.9 Hz, 1H), 4.50 (dd, J = 11.7 Hz, 2H), 4.10 (brd, J = 9.6 Hz, 1H), 3.92 (d, J = 6.6 Hz, 2H), 3.80 (s, 3H), 3.66 (s, 3H), 3.64-3.59 (m, 2H), 3.42-3.85 (m, 1H), 3.35-3.32 (m, 1H), 3.15 (s, 3H), 3.01-2.96 (m, 1H), 2.74 (d, 9.3Hz, 1H 2.70-2.67 (m, 1H), 2.08-2.03 (m, 1H), 1.92 (bs, 1H), 1.79-1.70 (m, 1H), 1.37 (s, 3H), 1.07 (d, J = 6.6Hz, 3H), 0.91 (s, 9H), 0.90 (s, 9H), 0.88 (s, 9H ), 0.85 (s, 9H), 0.16 (s, 3H), 0.12 (s, 3H), 0.08 (s, 3H), 0.03 (s, 6H), 0.02 (s, 6H), 0.00 (s, 3H).
MS (ESI) m / z: 994 (M + 23) ⁺ .
R _f = 0.34 (Hex: EtOAc, 4: 1).
27b: ¹ H NMR (300 MHz, CDCl ₃₎ δ 7.24 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 4.82 to 4 , 80 (m, 1H), 4.43 (q, J = 11.4Hz, 2H), 3.96-3.92 (m, 1H), 3.80 (s, 3H), 3.76- 3.75 (m, 1H), 3.66 (s, 3H), 3.69-3.58 (m, 3H), 3.46 (dd, J = 9.0, 6.3 Hz, 1H) , 3.31 (dd, J = 9.0, 7.2 Hz, 1H), 3.15 (s, 3H), 3.00-2.93 (m, 1H), 2.69 (d, J = 8.7 Hz, 1H), 2.69-2.62 (m, 1H), 2.02-1.94 (m, 2H), 1.80-1.73 (m, 1H), 1, 65 (s, 1H), 1.33 (s, 3H), 1.09 (d, J = 6.6 Hz, 3H), 0.91 (s, 9H), 0.89 (s, 9H), 0.87 (s, 9H), 0.85 (s, 9H), 0.17 (s, 3H), 0.12 (s, 3H), 0.10 (s, 3H), 0.07 (s , 3H), 0.05 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H), 0.02 (s, 3H).
MS (ESI) m / z: 994 (M + 23) ⁺
R _f = 0.46 (Hex: EtOAc, 4: 1).

Example 63: Compound 27c

To a solution of 27a (36 mg, 0.04 mmol) in CH ₂ Cl ₂ (4 mL) was added Dess-Martin periodinane (63 mg, 0.15 mmol) and a catalytic amount of NaHCO ₃ at 23 ° C. The reaction mixture was stirred at 23 ° C for 1.5 h. A saturated aqueous solution of NaHCO3 (10 mL) was added and the mixture extracted with CH ₂ Cl ₂ (3 x 10 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 10: 1) to give compound 27c (26 mg, 72%) as a pale yellow oil. This compound is also obtained by protecting 26c in quantitative yield with TBSOTf and lutidine under standard conditions.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.22 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 4.80 to 4.78 (m, 1H), 4.41 (q, J = 11.4Hz, 2H), 4.15 (d, J = 4.5Hz, 2H), 3.80 (s, 3H), 3.75 -3.67 (m, 2H), 3.64 (s, 3H), 3.61-3.50 (m, 3H), 3.39 (dd, J = 9.3, 7.2 Hz, 1H ), 3.29 (dd, J = 9.3, 6.6 Hz, 1H), 3.15 (bs, 3H), 2.99-2.96 (m, 1H), 2.67 (d, J = 9.3 Hz, 1H), 2.54 (br d, J = 5.1 Hz, 1H), 1.33 (s, 3H), 1.06 (d, J = 6.3 Hz, 3H ), 0.90 (s, 9H), 0.85 (s, 18H), 0.84 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H), 0.06 (s, 3H), 0.02 (s, 3H), 0.01 (s, 6H), -0.01 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 210.2, 172.5, 159.1, 130.2, 128.9, 113.7, 76.1, 72.6, 72.1, 67.0 , 64.0, 63.8, 61.5, 61.0, 60.8, 58.1, 55.1, 54.2, 36.7, 33.6, 29.6, 26.0, 25.9, 25.8, 25.7, 18, 2, 18.1, 18.0, 17.9, 15.1, 13.4, -4.8, -4.9, -4.9, -5.4, -5.5, -5, 5, -5.6.
MS (ESI) m / z: 992 (M + 23) ⁺ , 970 (M + 1) ⁺ .
[α] ²⁵ _D -45.1 (c 0.50, CH ₃ Cl).
R _f = 0.38 (Hex: EtOAc, 4: 1).

Example 64: Compound 27d

To a solution of 27b (77 mg, 0.08 mmol) in CH ₂ Cl ₂ (3 mL) was added Dess-Martin periodinane (63 mg, 0.15 mmol) and a catalytic amount of NaHCO ₃ at 23 ° C. The reaction mixture was stirred at 23 ° C for 1.5 h. A saturated aqueous solution of NaHCO3 (10 mL) was added and the mixture extracted with CH ₂ Cl ₂ (3 x 10 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 10: 1) to give compound 27d (51 mg, 66%) as a pale yellow oil. This compound is also obtained by protecting 26d in quantitative yield with TBSOTf and lutidine under standard conditions.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.23 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 4.47 (d, J = 12.0 Hz, 1H), 4.36 (d, J = 12.0 Hz, 1H), 3.99-3.83 (m, 3H), 3.80 (s, 3H), 3.69 -3.58 (m, 2H), 3.68 (s, 3H), 3.42-3.36 (m, 2H), 3.26 (dd, J = 9.3, 6.3 Hz, 1H , 3.17 (bs, 3H), 3.07 (dt, J = 9.3, 3.3 Hz, 1H), 2.90-2.87 (m, 1H), 2.59 (d, J = 9.0 Hz, 1H), 2.17 (br d, J = 14.1 Hz, 1H), 1.31 (s, 3H), 1.05 (d, J = 6.6 Hz, 3H ), 0.90 (s, 9H), 0.88 (s, 9H), 0.85 (s, 9H), 0.84 (s, 9H), 0.18 (s, 3H), 0.12 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), -0.01 (s, 6H), -0.02 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 209.2, 172.1, 159.2, 130.2, 129.0, 113.8, 76.3, 72.5, 71.8, 68.2 , 64.2, 63.0, 61.3, 60.9, 60.0, 59.3, 57.7, 55.1, 36.4, 34.0, 29.6, 26.4, 25 , 9, 25.8, 25.7, 18.7, 18.1, 17.9, 15.3, 12.4, -4.3, -4.4, -5.1, -5.2 , -5.5, -5.6, -5.7.
MS (ESI) m / z: 992 (M + 23) ⁺ .
[α] ²⁵ _D +47.6 (c 0.50, CH ₃ Cl).
R _f = 0.45 (Hex: EtOAc, 4: 1).

Example 65: Compound 28a

To a solution of 27c (390 mg, 0.4 mmol) in a mixture of CH ₂ Cl ₂ : H ₂ O (4: 0.2 mL) at 23 ° C was 2,3-dichloro-5,6-dicyano -1,4-benzoquinone (274 mg, 1.2 mmol) was added. The reaction mixture was stirred at 23 ° C for 18 min. A saturated aqueous solution of NaHCO ₃ (15 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (3 x 15 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in MeOH, NaBH ₄ (74 mg, 2 mmol) added and the reaction mixture was stirred at 23 ° C for 30 min. Then the reaction mixture was concentrated under reduced pressure. A saturated aqueous solution of NaHCO ₃ (20 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (3 x 30 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hex: EtOAc, 4: 1) to give compound 28a (220 mg, 65%) as a white solid.
¹ H NMR (300 MHz, CDCl ₃₎ δ 4.77 to 4.72 (m, 1H), 4.10 to 3.99 (m, 2H), 3.86 to 3.84 (m, 2H), 3.65 (s, 3H), 3.62-3.59 (m, 1H), 3.56-3.48 (m, 3H), 3.15 (s, 3H), 2.99-2, 95 (m, 1H), 2.76-2.75 (m, 1H), 2.58-2.55 (m, 1H), 2.52 (br d, J = 3.3 Hz, 1H), 2.46 (d, J = 9.3Hz, 1H), 1.67 (bs, 1H), 1.37 (s, 3H), 1.01 (d, J = 6.9Hz, 3H), 0.90 (s, 9H), 0.89 (s, 9H), 0.86 (s, 9H), 0.85 (s, 9H), 0.12 (s, 3H), 0.11 (s , 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H), 0 , 01 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 2H, 8, 172.1, 76.9, 67.1, 65.1, 64.8, 63.4, 61.5, 61.2, 61.1 , 58.5, 57.3, 36.6, 35.8, 32.0, 29.6, 26.0, 25.9, 25.8, 25.7, 18.2, 18.1, 17 , 9, 14.3, 13.7, -4.6, -4.8, -5.2, -5.4, -5.5, -5.6.
MS (ESI) m / z: 872 (M + 23) ⁺ .
[α] ²⁵ _D -32.9 (c 0.50, CH ₃ Cl).
R _f = 0.31 (Hex: EtOAc, 4: 1).

Example 66: compound 28b

To a solution of 27d (718 mg, 0.74 mmol) in a mixture of CH ₂ Cl ₂ : H ₂ O (10: 0.5 mL) at 23 ° C was 2,3-dichloro-5,6-dicyano -1,4-benzoquinone (504 mg, 2.22 mmol) was added. The reaction mixture was stirred at 23 ° C for 17 min. A saturated aqueous solution of NaHCO ₃ (15 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (3 x 15 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in MeOH, NaBH ₄ (110 mg, 3 mmol) added and the reaction mixture was stirred at 23 ° C for 20 min. Then the reaction mixture was concentrated under reduced pressure. A saturated aqueous solution of NaHCO ₃ (20 mL) was added and the mixture was extracted with CH ₂ Cl ₂ (3 x 30 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 4: 1) to give compound 28b (374 mg, 60%) as a white solid.
¹ H NMR (300 MHz, CDCl ₃₎ δ 4.75 to 4.72 (m, 1H), 4.02 to 3.92 (m, 2H), 3.88 (dd, J = 10.5, 3 , 9Hz, 1H), 3.71-3.65 (m, 1H), 3.67 (s, 3H), 3.61-3.54 (m, 2H), 3.49 (d, J = 6.3Hz, 1H), 3.45-3.39 (m, 1H), 3.16 (bs, 3H), 3.13-3.08 (m, 1H), 2.84 (br dd, J = 15.9, 8.7 Hz, 1H), 2.48 (d, J = 9.0 Hz, 1H), 2.46-2.44 (m, 1H), 1.72-1.67 (m, 1H), 1.31 (s, 3H), 1.09 (d, J = 6.6Hz, 3H), 0.90 (s, 9H), 0.89 (s, 9H), 0 , 86 (s, 9H), 0.85 (s, 9H), 0.16 (s, 3H), 0.12 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 212.6, 172.0, 76.4, 67.6, 65.2, 65.0, 62.9, 61.2, 61.1, 60.8 , 59.9, 59.5, 37.1, 36.2, 32.0, 29.6, 26.0, 25.9, 25.8, 25.6, 18.3, 18.1, 18 , 0, 18.0, 14.4, 13.5, -3.6, -4.4, -4.8, -4.9, -5.0, -5.5, -5.6, -5.7.
MS (ESI) m / z: 872 (M + 23) ⁺ .
[α] ²⁵ _D +21.6 (c 0.52, CH ₃ Cl).
R _f = 0.31 (Hex: EtOAc, 4: 1).

Example 67: Compound 29a

To a solution of 28a (162 mg, 0.19 mmol) in CH ₂ Cl ₂ (5 mL) was added Dess-Martin periodinane (202 mg, 0.47 mmol) and a catalytic amount of NaHCO ₃ at 23 ° C. The reaction mixture was stirred at 23 ° C for 40 min. A saturated aqueous solution of NaHCO ₃ (15 mL) was added and the mixture extracted with CH ₂ Cl ₂ (3 x 20 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure, whereupon the corresponding aldehyde is obtained (R _f = 0.32, hex: EtOAc, 4: 1). In the meantime, at 0 ° C, to a suspension of ethyltriphenylphosphonium bromide (565 mg, 1.94 mmol) in toluene (7 mL) was added potassium tert -butoxide (1.24 mL, 1.0 M in THF, 1.24 mmol ) was added. An orange solution resulted, which was stirred at 0 ° C for 25 min and then cooled to -78 ° C. Subsequently, a solution of the fresh aldehyde crude product in toluene (5 mL) was added dropwise to the previous suspension at -78 ° C and the mixture was then brought to 23 ° C within 14 h. The reaction mixture was diluted with CH ₂ Cl ₂ (20 mL) and washed with a saturated NaHCO ₃ solution (30 mL). The organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 20: 1) to give compound 29a (105 mg, 64% for two steps) as a white solid.
¹ H NMR (300 MHz, CDCl ₃₎ δ 5.52 to 5.46 (m, 1H), 5.26 to 5.19 (m, 1H), 4.88 to 4.87 (m, 1H), 4.20-4.09 (m, 2H), 3.70-3.65 (m, 1H), 3.64 (s, 3H), 3.60-3.57 (m, 3H), 3, 42 (d, J = 8.4 Hz, 1H), 3.15 (bs, 3H), 2.79-2.75 (m, 1H), 2.58 (d, J = 9.6 Hz, 1H ), 2.43-2.39 (m, 2H), 1.62 (dd, J = 6.6, 1.5 Hz, 3H), 1.29 (s, 3H), 1.10 (d, J = 6.6 Hz, 3H), 0.91 (s, 9H), 0.86 (s, 9H), 0.85 (s, 9H), 0.84 (s, 9H), 0.10 ( s, 3H), 0.09 (s, 6H), 0.08 (s, 3H), 0.01 (s, 3H), 0.00 (s, 3H), -0.01 (s, 3H) , -0.02 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 211.0, 171.9, 130.5, 124.0, 66.6, 64.8, 62.6, 61.9, 61.6, 60.6 , 57.0, 53.7, 36.2, 31.1, 29.2, 25.7, 25.5, 25.4, 25.3, 18.4, 17.8, 17.7, 17.6, 12.7, 11.8, -5 , 1, -5.2, -5.3, -5.4, -5.8, -5.9, -6.0.
MS (ESI) m / z: 882 (M + 23) ⁺ .
[α] ²⁵ _D -26.1 (c 0.50, CH ₂ Cl ₂ ).
R _f = 0.44 (Hex: EtOAc, 4: 1).

Example 68: Compound 29b

To a solution of 28b (318 mg, 0.37 mmol) in CH ₂ Cl ₂ (8 mL) was added Dess-Martin periodinane (397 mg, 0.93 mmol) and a catalytic amount of NaHCO ₃ at 23 ° C. The reaction mixture was stirred at 23 ° C for 40 min. A saturated aqueous solution of NaHCO3 (30 mL) was added and the mixture extracted with CH ₂ Cl ₂ (3 x 40 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure, whereupon the corresponding aldehyde is obtained. In the meantime, at 0 ° C to a suspension of ethyltriphenylphosphonium bromide (1.1 g, 3.77 mmol) in toluene (12 mL) of potassium tert-butoxide (2.43 mL, 1 M in THF, 2.34 mmol ) was added. An orange solution was obtained, which was stirred at 0 ° C for 25 min and then cooled to -78 ° C. Subsequently, a solution of the fresh aldehyde crude product in toluene (6 mL) was added dropwise to the previous suspension at -78 ° C and the mixture was then brought to 23 ° C within 15 h. The reaction mixture was diluted with CH ₂ Cl ₂ (20 mL) and washed with a saturated NaHCO ₃ solution (30 mL). The organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 20: 1) to give compound 29b (195 mg, 60% for two steps) as a white solid.
¹ H NMR (300 MHz, CDCl ₃₎ δ 5.50 to 5.42 (m, 1H), 5.29 to 5.25 (m, 1H), 4.81 to 4.78 (m, 1H), 3.93 (dd, J = 11.4, 3.6Hz, 1H), 3.81 (m, 2H), 3.67 (s, 3H), 3.64-3.56 (m, 2H) , 3.43-3.39 (m, 1H), 3.17 (bs, 3H), 3.03-3.00 (m, 1H), 2.96-2.88 (m, 1H), 2 , 65 (d, J = 9.0 Hz, 1H), 2.46-2.35 (m, 1H), 2.10 (br d, J = 14.7 Hz, 1H), 1.61 (dd , J = 6.9, 1.8 Hz, 1H), 1.28 (s, 3H), 1.11 (d, J = 6.9 Hz, 3H), 0.90 (s, 9H), 0 , 87 (s, 9H), 0.85 (s, 9H), 0.84 (s, 9H), 0.18 (s, 3H), 0.14 (s, 3H), 0.08 (s, 3H), 0.06 (s, 3H), 0.06 (s, 3H), 0.01 (s, 3H), -0.02 (s, 3H), -0.03 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 209.0, 172.0, 131.0, 124.2, 76.3, 68.1, 65.0, 62.6, 61.4, 61.3 , 59.6, 59.4, 57.2, 36.3, 31.8, 29.7, 26.4, 25.9, 25.8, 25.7, 18.9, 18.7, 18 , 1, 18.0, 17.9, 13.2, 11.9, -4.3, -4.4, -5.1, -5.2, -5.4, -5.5, - 5.6.
MS (ESI) m / z: 882 (M + 23) ⁺ .
[α] ²⁵ _D + 70.2 (c 0.50, CH ₂ Cl ₂ ).
R _f 0.77 (Hex: EtOAc, 4: 1).

Example 69: Compound 30a

To a solution of 29a (80 mg, 0.093 mmol) in TIM (1.5 mL) at 23 ° C was added BrMgEt (0.28 mL, 1 M in THF, 0.28 mmol). The reaction mixture was stirred at 23 ° C for 3 h. A saturated aqueous solution of NaHCO ₃ (10 mL) was added and the mixture extracted with CH ₂ Cl ₂ (3 x 15 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 20: 1) to give 30a (54 mg, 71%) as a white solid.
¹ H NMR (300 MHz, CDCl ₃₎ 5.54 to 5.44 (m, 1H), 5.26 to 5.18 (m, 1H), 4.83 (ddd, J = 9.6, 4, 2, 21, Hz, 1H), 4.13 (dd, J = 9.6, 7.2 Hz, 1H), 4.05 (dd, J = 9.6, 3.9 Hz, 1H), 3 , 67 (dd, J = 8.7, 6.6 Hz, 1H), 3.59-3.57 (m, 2H), 3.38 (d, J = 9.0 Hz, 1H), 2, 75-2.70 (m, 1H), 2.55 (d, J = 9.3 Hz, 1H), 2.46-2.43 (m, 5H), 1.62 (dd, J = 6, 6, 1.8 Hz, 3H), 1.28 (s, 3H), 1.10 (d, J = 6.3 Hz, 3H), 1.01 (t, J = 7.2 Hz, 3H) , 0.91 (s, 9H), 0.86 (s, 9H), 0.85 (s, 9H), 0.82 (s, 9H), 0.10 (s, 3H), 0.09 ( s, 6H), 0.08 (s, 3H), 0.01 (s, 3H), 0.00 (s, 3H), -0.01 (s, 3H), -0.03 (s, 3H ).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 212.5, 209.2, 131.1, 124.7, 78.2, 66.6, 65.5, 63.2, 62.6, 62.4 , 57.5, 54.3, 53.6, 47.3, 36.7, 31.8, 29.9, 26.3, 26.1, 26.0, 19.0, 18.5, 18 , 3, 18,2, 13,4, 12,4, 7,8, -4,3, -4,4, -4,7, -4,8, -5,1, -5,2, - 5.3.
MS (ESI) m / z: 851 (M + 23) ⁺ .
[α] ²⁵ _D -25.4 (c 0.50, CH ₂ Cl ₂ ).
R _f = 0.86 (Hex: EtOAc, 4: 1).

Example 70: Compound 30b

To a solution of 29b (110 mg, 0.13 mmol) in THF (1.5 mL) at 23 ° C was added BrMgEt (0.38 mL, 1 M in THF, 0.38 mmol). The reaction mixture was stirred at 23 ° C for 4 h. A saturated aqueous solution of NaHCO ₃ (10 mL) was added and the mixture extracted with CH ₂ Cl ₂ (3 x 15 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 20: 1) to give Compound 30b (70 mg, 65%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 5.52 to 5.41 (m, 1H), 5.28 to 5.20 (m, 1H), 4.76 to 4.72 (m, 1H), 3.85-3.73 (m, 3H), 3.70 (d, J = 10.2Hz, 1H), 3.48-3.41 (m, 2H), 3.05-3.00 ( dt, J = 10.2, 3.3 Hz, 1H), 2.80 (dd, J = 15.6, 10.5 Hz, 1H), 2.64 (d, J = 9.3 Hz, 1H ), 2.45-2.40 (m, 3H), 2.38-2.12 (m, 1H), 1.61 (dd, J = 6.9, 1.8 Hz, 3H), 1, 29 (s, 3H), 1.11 (d, J = 6.3 Hz, 3H), 1.01 (t, J = 7.2 Hz, 3H), 0.89 (s, 18H), 0, 84 (s, 18H), 0.19 (s, 3H), 0.14 (s, 3H), 0.05 (s, 3H), 0.03 (s, 6H), 0.01 (s, 3H ), 0.00 (s, 3H), -0.04 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 209.5, 209.3, 131.0, 124.3, 76.0, 67.6, 64.9, 62.4, 61.3, 59.8 , 58.9, 57.3, 45.5, 38.1, 31.9, 29.7, 26.3, 25.9, 25.8, 25.7, 19.0, 18.7, 18 , 1, 18.0, 17.8, 13.3, 11.9, 7.4, -4.1, -4.2, -5.1, -5.2, -5.4, -5 , 5, -5,6, -5,7.
MS (ESI) m / z: 851 (M + 23) ⁺ .
[α] ²⁵ _D +80.9 (c 0.50, CH ₂ Cl ₂ ).
R _f = 0.71 (hex: EtOAc, 4: 1).

Example 71: Compounds 31a and 31c

Following the procedure described in Example 50, 30a (48 mg, 0.058 mmol) was converted to a tautomeric equilibrium of 31a and 31c after purification of the crude product by flash column chromatography (Hex: EtOAc, from 4: 1 to 1: 1) (20 mg, 70%, colorless oil).
¹ H NMR (500 MHz, CDCl ₃ ) (major product data) δ 5.55-5.49 (m, 1H), 5.29-5.24 (m, 1H), 4.28 (ddd, J = 15.5, 11.0, 4.5 Hz, 1H), 3.97 (dd, J = 11.5, 11.5 Hz, 2H), 3.76 (dd, 11.5, 3.5 Hz , 1H), 3.67-3.65 (m, 1H), 3.62 (d, J = 10.0 Hz, 1H), 3.35-3.31 (m, 1H), 2.86- 2.80 (m, 1H), 2.60 (d, J = 9.0 Hz, 1H), 2.44-2.37 (m, 1H), 2.09 (dd, J = 12.5, 4.5 Hz, 1H), 1.70-1.65 (m, 2H), 1.62 (dd, J = 7.0, 2.0 Hz, 3H), 1.45 (br t, J = 11.5 Hz, 1H), 1.30 (s, 3H), 1.11 (d, J = 7.0 Hz, 3H), 0.96 (t, J = 7.5 Hz, 3H), 0 , 89 (s, 9H), 0.16 (s, 3H), 0.05 (s, 3H).
¹³ C NMR (125 MHz, CDCl ₃ ) (main product data) δ 214.7, 130.5, 124.8, 98.7, 78.2, 66.9, 65.0, 61.8, 60, 5, 59.6, 59.2, 57.7, 39.9, 35.6, 31.4, 26.1, 18.7, 18.4, 13.3, 11.6, 7.4, -4.4, -4.7.
MS (ESI) m / z: 509 (M + 23) ⁺ , 451 (M + 1-2 × H ₂ O) ⁺ .
R _f 0.4 (Hex: EtOAc, 1: 2).

Example 72: compounds 31b and 31d

According to the procedure described in Example 50, 30b (45 mg, 0.054 mmol) after purification of the crude product by flash column chromatography (hex: EtOAc, from 4: 1 to 1: 1) was converted to a tautomeric equilibrium of 31b and 31d (13 mg, 50%, colorless oil).
¹ H NMR (500 MHz, CDCl ₃ ) (main product data) δ 5.59-5.46 (m, 1H), 5.28 (m, 1H), 4.62 (bs, 1H), 4.22 (dd, J = 11.5, 11.5 Hz, 1H), 4.10 (dd, J = 12.0, 5.0 Hz), 3.70-3.60 (m, 2H), 3, 48 (d, J = 10.0 Hz, 1H), 3.24-3.17 (m, 1H), 2.94 (ddd, J = 11.5, 5.0, 2.0 Hz, 1H) , 2.61 (d, J = 9.5 Hz, 1H), 2.47-2.41 (m, 1H), 2.03 (dd, J = 14.5, 3.5 Hz,), 1 , 66 (dd, J = 7.0, 1.5 Hz, 3H), 1.63-1.61 (m, 2H), 1.58 (dd, J = 14.0, 3.0 Hz, 1H ), 1.32 (s, 3H), 1.14 (d, J = 6.0 Hz, 3H), 0.97 (t, J = 7.5 Hz, 3H), 0.87 (s, 9H ), 0.15 (s, 3H), 0.00 (s, 3H). ¹³ C NMR (125 MHz, CDCl ₃ ) (main product data) δ 216.3, 130.5, 124.9, 97.2, 78.4, 65.9, 65.2, 62.0, 60, 7, 55,7, 55,4, 54,7, 37,1, 34,2, 31,4, 26,0, 18,7, 18,2, 13,3, 11,4, 7,4, -4,3, -5,2.
MS (ESI) m / z: 509 (M + 23) ⁺ , 451 (M + 1-2 × H ₂ O) ⁺ .
R _f 0.42 (Hex: EtOAc, 1: 2).

Example 73: Compounds 3c and 4c

According to the procedure described in Example 52, 31a (48 mg, 0.058 mmol) after purification of the crude product by flash column chromatography (Hex: EtOAc, from 4: 1 to 0: 1) to a tautomeric equilibrium of 3c and 4c transferred (5 mg, 22%).
¹ H NMR (500 MHz, CDCl ₃ ) (major product data) δ 5.56-5.49 (m, 1H), 5.28-5.23 (m, 1H), 4.36 (ddd, J = 15.0, 11.0, 5.0 Hz, 1H), 3.97-3.66 (m, 4H), 3.62 (d, J = 10.0 Hz, 1H), 3.25-3 , 18 (m, 1H), 2.98 (ddd, J = 14.0, 10.0, 4.0 Hz, 1H), 2.78 (d, J = 9.0 Hz, 1H), 2, 45-2.40 (m, 1H), 2.09 (dd, J = 13.0, 5.0 Hz, 1H), 1.67 (q, J = 7.5 Hz, 2H), 1.63 (dd, J = 1.5 Hz, 7 Hz, 3H), 1.48-1.42 (m, 1H), 1.33 (s, 3H), 1.12 (dJ = 7.0 Hz, 3H), 0.96 (t, J = 7.5 Hz, 3H).
¹³ C NMR (125 MHz, CDCl ₃ ) (main product data) δ 215.4, 130.0, 125.0, 98.7, 77.3, 67.0, 62.8, 60.8, 60, 0, 59.0, 40.1, 35.5, 31.3, 23.9, 19.7, 18.6, 13.3, 11.3, 7.4.
MS (ESI) m / z: 767 (2 x M + 23) ⁺ , 395 (M + 23) ⁺ , 337 (M + 1-2 x H ₂ O) ⁺ .
R _f = 0.16 (Hex: EtOAc, 1: 2).

Example 74: Compounds 3d and 4d

According to the procedure described in Example 52, 31b (150 mg, 0.18 mmol) was converted to a tautomeric equilibrium of 3d and 4d after purification of the crude product by flash column chromatography (Hex: EtOAc, from 4: 1 to 0: 1).
¹ H NMR (500 MHz, CH ₃ OD (main product data) δ 5.57-5.51 (m, 1H), 5.32-5.26 (m, 1H), 4.80 (m, 1H) , 4.26 (dd, J = 11.5, 11.5 Hz, 1H), 3.98-3.60 (m, 3H), 3.31-3.29 (m, 1H), 3.24 (d, J = 10Hz, 1H), 2.80 (ddd, J = 11.5, 4.5, 2.5Hz, 1H), 2.59 (d, J = 9.5Hz, 1H) , 1.95 (dd, J = 14.0, 3.5 Hz, 1H), 1.75 (dd, J = 14.5, 3.0 Hz, 1H), 1.65 (dd, J = 6) , 5, 15, Hz, 3H), 1.56 (q, J = 7.5 Hz, 2H), 1.34 (s, 3H), 1.10 (d, J = 7.0 Hz, 3H) , 0.92 (t, J = 7.5 Hz, 3H).
¹ H NMR (500 MHz, CDCl ₃ ) (main product data) δ 5.56-5.50 (m, 1H), 5.36 (s, 1H), 5.27-5.21 (m, 1H) , 4.76 (bs, 1H), 4.29 (dd, J = 11.5, 11.5 Hz, 1H), 3.87 (dd, J = 12.5, 4.0 Hz, 1H), 3.73-3.62 (m, 3H), 3.46 (d, J = 10.0 Hz, 1H), 2.90 (ddd, J = 11.5, 4.5, 2.0 Hz, 1H), 2.74 (d, J = 9.5Hz, 1H), 2.01 (dd, J = 13.5, 3.5Hz, 1H), 1.70 (dd, J = 14.0 , 2.5 Hz, 1H), 1.62 (dd, J = 7.0, 2.0 Hz, 3H), 1.61-1.59 (m, 2H), 1.34 (s, 3H) , 1.11 (d, J = 6.5 Hz, 3H), 0.95 (t, J = 7.0 Hz, 3H).
¹³ C NMR (125 MHz, CDCl ₃ ) (main product data) δ 214.9, 130.0, 125.1, 96.9, 77.1, 67.1, 65.4, 62.8, 60, 9, 55.3, 54.9, 52.7, 37.4, 34.2, 31.3, 18.6, 13.3, 11.4, 7.5.
MS (ESI) m / z: 767.2 (2 x M + 23) ⁺ , 395.3 (M + 23) ⁺ , 377.3 (M + 23-H ₂ O) ⁺ , 337 (M + 1) 2 × H ₂ O) ⁺ , 319.3 (M + 1-3 × H ₂ O) ⁺ .
R _f = 0.22 (Hex: EtOAc, 1: 2).

Example 75: Connection 32

This compound was obtained as a by-product in the preparation of 34 from 11a. To a solution of 11a (1.72 g, 2.69 mmol) in acetone (10 mL) was added dimethoxypropane (10 mL) and camphorsulfonic acid (94 mg, 0.4 mmol) and the mixture was stirred at 23 ° C for 1 Stirred (until DC indicated the complete consumption of the reactant). Et ₃ N (0.56 mL, 4 mmol) was then added and the mixture stirred for 30 min. Solvents were removed under reduced pressure and the mixture was subjected to flash column chromatography on silica gel (hex: EtOAc, from 10: 1 to 3: 1) to give furan 32 (0.6 g, 35%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.23 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.72 to 5.65 (m, 1H), 5.09-5.06 (m, 2H), 4.42 (s, 2H), 4.44-4.39 (m, 1H), 3.90 (dd, J = 10 , 0, 2.0 Hz, 1H), 3.84-3.78 (m, 2H), 3.80 (s, 3H), 3.60 (dd, J = 6.0, 5.5 Hz, 1H), 3.51-3.42 (m, 3H), 3.36-3.32 (m, 2H), 2.76-2.73 (m, 1H), 2.63-2.58 ( m, 1H), 2.13-2.09 (m, 1H), 1.98 (d, J = 4.5Hz, 1H), 1.02 (d, J = 6.8Hz, 3H), 0.99 (s, 3H), 0.92 (s, 9H), 0.90 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H), 0.09 (s , 3H), 0.07 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 159.1, 137.4, 130.5, 129.1, 116.3, 113.7, 83.6, 78.7, 77.7, 77.1 , 75.4, 72.7, 64.9, 58.6, 55.2, 49.6, 34.4, 25.8, 25.7, 18.1, 18.0, 17.5, 12 , 5, -4.7, -5.1, -5.5 -5.6.
MS (ESI) m / z: 661.4 (M + 23) ⁺ .
R _f = 0.35 (Hex: EtOAc; 4: 1).

Example 76: compounds 33 and 42

To a solution of furan 32 (246 mg, 0.346 mmol) in CH ₂ Cl ₂ (10 mL) and water (0.5 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (236 mg, 1.04 mmol) was added and the reaction mixture stirred vigorously for 1 h at 23 ° C. The reaction was hydrolyzed by addition of aqueous NaHCO ₃ solution (20 mL) and the solution extracted with CH ₂ Cl ₂ (2 × 20 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was dissolved in MeOH (5 mL) and treated with NaBH4 (30 mg) for 30 min at 23 ° C. Thereafter, the solvents were removed under reduced pressure and the residue was dissolved in CH ₂ Cl ₂ , hydrolyzed with aqueous NH ₄ Cl and extracted with CH ₂ Cl ₂ (2 x 20 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hex: EtOAc, from 4: 1 to 2: 1) to give compound 33 (88 mg, 40%) and 42 (77 mg, 42%) as colorless oils.
33: ¹ H NMR (300 MHz, CDCl ₃₎ δ 5.82 to 5.75 (m, 1H), 5.46 (s, 1H), 5.13 to 5.09 (s, 2H), 4, 48 (d, J = 6.5 Hz, 1H), 4.07-4.04 (m, 1H), 3.99 (dd, J = 4.5, 4.0 Hz, 1H), 3.97 3.94 (m, 1H), 3.91 (d, J = 2.5 Hz, 1H), 3.88-3.79 (m, 2H), 3.81 (s, 3H), 3, 62 (dd, J = 6.0, 5.0 Hz, 1H), 3.50-3.43 (m, 1H), 3.28-3.22 (m, 1H), 2.76-2, 67 (m, 2H), 1.76-1.71 (m, 1H), 1.26 (d, 7.0 Hz, 3H), 1.08 (s, 3H), 0.91 (s, 9H 0.87 (s, 3H), 0.08 (s, 3H), 0.04 (s, 3H), -0.07 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 159.8, 137.4, 131.3, 127.4, 116.3, 113.5, 102.1, 86.4, 83.4, 79.4 , 77.0, 75.4, 65.1, 58.7, 55.2, 49.9, 46.2, 30.6, 29.7, 25.8, 18.6, 18.1, 13 , 3, -4,3, -5,2, -5,4, -5,5.
MS (ESI) m / z: 659.2 (M + 23) ⁺ .
R _f = 0.31 (Hex: EtOAc, 4: 1).
42: ¹ H NMR (300 MHz, CDCl ₃₎ δ 5.68 to 5.55 (m, 1H), 5.18 to 5.12 (m, 2H), 4.41 (d, J = 6.7 Hz, 1H), 3.94-3.77 (m, 3H), 3.70-3.36 (m, 3H), 3.14 (d, J = 8.6Hz, 1H), 2.82-2.77 (m, 1H), 2.64-2 , 59 (m, 1H), 2.04-2.03 (m, 1H), 1.89-1.82 (m, 1H), 1.04 (s, 3H), 0.97 (d, J = 6.7 Hz, 3H), 0.92 (s, 9H), 0.90 (s, 9H), 0.13 (s, 3H), 0.11 (s, 6H), 0.09 (s , 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 136.3, 118.4, 82.9, 80.3, 79.7, 79.1, 66.4, 64.7, 58.4, 49.5 , 47.0, 39.1, 26.1, 26.0, 18.4, 18.3, 16.5, 15.2, -4.4, -5.0, -5.2, -5 ; 3.
MS (ESI) m / z: 541.2 (M + 23) ⁺ , 519.3 (M + 1) ⁺ .
R _f = 0.06 (Hex: EtOAc, 4: 1).

Example 77: compound 34

To a solution of 11a (1.72 g, 2.69 mmol) in acetone (10 mL) was added dimethoxypropane (10 mL) and camphorsulfonic acid (94 mg, 0.4 mmol) and the mixture was stirred at 23 ° C for 1 Stirred (until DC indicated the complete consumption of the reactant). Then Et ₃ N (0.56 mL, 4 mmol) was added and the mixture was stirred for 30 min. Solvents were removed under reduced pressure and the mixture subjected to flash column chromatography on silica gel (hex: EtOAc, from 10: 1 to 3: 1) to give acetonide 34 (1.16 gm, 64%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.20 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.30 to 6.17 (m, 1H), 5.13 (dd, J = 10.2, 2.1Hz, 1H), 5.09 (dd, J = 16.8, 2.1Hz, 1H), 4.37 ( ss, J = 15.6, 1.7Hz, 2H), 4.19 (dd, J = 7.2, 2.1Hz, 1H), 4.10 (dd, J = 11.4, 2, 7Hz, 1H), 3.80 (s, 3H), 3.68 (d, J = 6.0Hz, 1H), 3.64-3.57 (m, 2H), 3.49 (dd, J = 10.2, 6.0Hz, 1H), 3.39-3.28 (m, 2H), 2.55 (d, J = 9.3Hz, 1H), 2.27 (d, J = 9.6 Hz, 1H), 2.04-1.72 (m, 2H), 1.43 (s, 3H), 1.36 (s, 3H), 1.27 (3, 3H), 1 , 06 (d, J = 6.9 Hz, 3H), 0.92 (s, 9H), 0.86 (s, 9H), 0.12 (s, 3H), 0.07 s, 3H), 0.00 (s, 3H), -0.01 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 159.1, 137.2, 130.1, 129.1, 117.1, 113.7, 98.8, 76.5, 72.9, 72.7 , 67.8, 66.2, 64.8, 64.5, 58.4, 55.2, 44.9, 44.0, 33.5, 29.8, 26.1, 25.9, 18 , 8, 18.3, 18.0, 14.9, 13.2, -4.5, -4.6, -5.3, -5.5.
MS (ESI) m / z: 701 (M + 23) ⁺ .
R _f = 0.67 (Hex: EtOAc, 4: 1).

Example 78: Compound 35a

To a solution of 14a (32 mg, 0.037 mmol) in acetone (1.5 mL) was added dimethoxypropane (1.5 mL) and camphorsulfonic acid (0.85 mg, 0.0037 mmol) and the mixture was stirred at 23 ° C stirred for 1 h (until DC indicated the complete consumption of the educt). Et ₃ N (14 μL, 0.01 mmol) was then added and the mixture stirred for 30 min.

Solvents were removed under reduced pressure and the mixture subjected to flash column chromatography on silica gel (hex: EtOAc, 4: 1) to give acetonide 35a (27 mg, 81%) as a colorless oil.
^1H NMR (300 MHz, CDCl ₃₎ δ 7.25 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.49 to 4.38 (m, 3H), 3.82-3.74 (m, 2H), 3.80 (s, 3H), 3.70-3.30 (m 3H), 3.18 (s, 3H), 2 , 96 (d, J = 9.1 Hz, 1H), 2.74-2.60 (m, 1H), 2.52 (d, J = 8.6 Hz, 1H), 2.56-2, 46 (m, 1H), 2.42-2.36 (m, 1H), 2.04-1.90 (m, 1H), 1.82-1.58 (m 2H), 1.32 (s , 3H), 1.30 (s, 3H), 1.25 (s, 3H), 1.12 (d, J = 6.5 Hz, 3H), 0.92 (s, 9H), 0.89 (s, 9H), 0.87 (s, 9H), 0.17 (s, 3H), 0.10 (s, 3H), 0.08 (s, 3H), 0.05 (s, 3H) , 0.03 (s, 3H), 0.02 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 173.1, 159.4, 130.7, 129.4, 114.0, 100.9, 78.2, 73.0, 72.2, 67.2 , 65.6, 64.0, 63.4, 61.4, 60.8, 59.8, 55.5, 50.5, 46.5, 39.0, 33.4, 30.0, 26 , 5, 26.3, 25.2, 25.5, 18.7, 18.4, 18.3, 15.4, 12.0, -3.4, -4.8, -5.2, -5.4, -5.7.
MS (ESI) m / z: 921 (M + 23) ⁺ .
R _f = 0.24 (Hex: EtOAc, 4: 1).

Example 79: compound 35b

To a solution of 14b (40 mg, 0.047 mmol) in acetone (1.5 mL) was added dimethoxypropane (1.5 mL) and camphorsulfonic acid (1 mg, 0.0047 mmol) and the mixture was stirred at 23 ° C for 1 Stirred (until DC indicated the complete consumption of the reactant). Then Et ₃ N (14 μL, 0.01 mmol) was added and the mixture was stirred for 30 min. Solvents were removed under reduced pressure and the mixture subjected to flash column chromatography on silica gel (Hex: EtOAc, 4: 1) to give acetonide 35b (40 mg, 95%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.25 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.42 (dd, J = 22.7, 11.3 Hz, 2H), 4.36-4.20 (m, 1H), 4.05 (d, J = 11.5 Hz, 1H), 3.80 (s, 3H) , 3.82-3.74 (m, 1H), 3.70 (s, 3H), 3.52-3.42 (m, 4H), 3.38-3.33 (m, 1H) 3, 19 (s, 3H), 3.07 (d, J = 8.0 Hz, 1H) 2.70 (br s, 1H), 2.48 (d, J = 8.6 Hz, 1H), 2, 04-1.92 (m, 2H), 1.86-1.76 (m, 1H), 1.28 (s, 3H), 1.27 (s, 3H), 1.25 (s, 3H) , 1.10 (d, J = 6.7 Hz, 3H), 0.91 (s, 9H), 0.90 (s, 9H), 0.87 (s, 9H), 0.15 (s, 3H), 0.09 (s, 3H), 0.07 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 172.8, 159.4, 130.7, 129.4, 114.0, 97.7, 77.5, 73.1, 72.6, 69.4 , 67.7, 64.2, 63.9, 61.7, 61.4, 60.0, 55.5, 47.4, 42.7, 33.3, 30.0, 29.9, 26 , 4, 26.3, 26.2, 20.2, 18.6, 18.4, 18.3, 15.3, 12.0, -3.4, -3.6, -4.8, -5.2, -5.4, -5.7. MS (ESI) m / z: 921 (M + 23) ⁺ .
R _f = 0.27 (Hex: EtOAc, 4: 1).

Example 80: Compound 36a

To a solution of 38a (26 mg, 0.035 mmol) in acetone (1 mL) was added dimethoxypropane (1 mL) and camphorsulfonic acid (1 mg, 0.0047 mmol) and the mixture was stirred at 23 ° C for 1 h (to DC indicated the complete consumption of the educt). Et ₃ N (14 μL, 0.01 mmol) was then added and the mixture stirred for 30 min. Solvents were removed under reduced pressure and the mixture subjected to flash column chromatography on silica gel (HEx: EtOAc, 3: 1) to give acetonide 36a (18 mg, 70%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.20 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.784 to 5.71 (m , 1H), 5.11-4.97 (m, 2H), 4.41-4.30 (m, 2H), 4.12 (dd, J = 7.0, 5.2 Hz, 1H), 3.96-3.90 (m, 1H), 3.81 (s, 3H), 3.68 (s, 3H), 3.70-3.61 (m, 2H), 3.46-3, 41 (m, 1H), 3.33 (d, J = 6.7Hz, 2H), 3.17 (s, 3H), 2.82-2.74 (m, 1H), 2.56 (i.e. , J = 9.3 Hz, 1H), 2.54-2.49 (m, 1H), 2.41-2.34 (m, 1H), 1.85-1.60 (m, 2H), 1.34 (s, 3H), 1.29 (s, 3H), 1.25 (s, 3H), 1.07 (d, J = 6.7Hz, 3H), 0.94 (s, 9H ), 0.86 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H), 0.01 (s, 3H), 0.00 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 172.8, 159.4, 137.1, 130.5, 129.3, 118.7, 114.0, 101.6, 73.1, 72.8 , 68.9, 66.2, 65.2, 64.7, 61.4, 59.0, 55.5, 53.5, 43.8, 33.8, 29.9, 26.5, 26 , 2, 25.0, 24.1, 18.7, 18.3, 15.3, 13.8, -4.1, -4.3, -5.0, -5.1.
MS (ESI) m / z: 802 (M + 23) ⁺ , 780 (M + 1) ⁺ . R _f = 0.18 (Hex: EtOAc, 4: 1).

Example 81: Compound 36b

To a solution of 38b (34 mg, 0.046 mmol) in acetone (1 mL) was added dimethoxypropane (1 mL) and camphorsulfonic acid (1 mg, 0.0047 mmol) and the mixture was stirred at 23 ° C for 1 h (to DC indicated the complete consumption of the educt). Et ₃ N (14 μL, 0.046 mmol) was then added and the reaction mixture stirred at 23 ° C for 30 min. Solvents were removed under reduced pressure and the mixture was subjected to flash column chromatography on silica gel (hex: EtOAc, 3: 1) to give acetonide 36b (33 mg, 92%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.20 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.95 to 6.08 (m, 1H), 5.02-5.25 (m, 2H), 4.42-4.53 (m, 1H), 4.38 (s, 2H), 4.26-4.28 (m , 1H), 3.80 (s, 3H), 3.58-3.69 (m, 2H), 3.65 (s, 3H), 3.41-3.46 (m, 1H), 3, 32 (d, J = 6.7 Hz, 2H), 3.14 (s, 3H), 2.59-2.67 (m, 1H), 2.55 (d, J = 9.1 Hz, 1H ), 2.31 (d, J = 10.4 Hz, 1H), 2.17-2.29 (m, 1H), 1.64-1.50 (m, 2H), 1.47 (s, 3H), 1.33 (s, 3H), 1.25 (s, 3H), 1.06 (d, J = 6.7Hz, 3H), 0.92 (s, 9H), 0.86 ( s, 9H), 0.11 (s, 3H), 0.08 (s, 3H), 0.00 (s, 3H), -0.02 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 171.2, 159.4, 134.5, 130.6, 129.3, 113.9, 99.5, 76.5, 73.0, 72.9 , 69.2, 64.4, 61.4, 58.7, 55.4, 48.3, 45.5, 36.6, 33.7, 30.1, 29.9, 26.3, 26 , 1, 19.7, 18.6, 15.2, 13.6, -4.3, -5.1, -5.2.
MS (ESI) m / z: 780.7 (M + 1) ⁺ , 802.7 (M + 23) ⁺ .
R _f = 0.20 (Hex: EtOAc, 4: 1).

Example 82: Connection 37

To a solution of diol 11a (300 mg, 0.47 mmol) in CH ₂ Cl ₂ (10 mL) was added Dess-Martin periodinane (DMP) (0.24 g, 0.56 mmol) and the mixture was at 0 C. for 1 h and for a further 30 min at 23.degree. A saturated aqueous solution of NaHCO ₃ (20 mL) was added and the mixture extracted with CH ₂ Cl ₂ (2 x 20 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue 37 was used without further purification in the next step.
¹ H NMR (300 MHz, CDCl _3): δ 9.45 (d, J = 2.6 Hz, 1H), 7.21 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6Hz, 2H), 5.75-5.84 (m, 1H), 5.19-5.37 (m, 2H), 4.55-4.58 (m, 1H), 4 , 40 (s, 2H), 3.81 (s, 3H), 3.45-3.88 (m, 4H), 3.38 (d, J = 8.7 Hz, 2H), 3.15- 3.20 (m, 1H), 2.55 (d, J = 9.1Hz, 1H), 1.67-1.84 (m, 2H), 1.25 (s, 3H), 1.06 (d, J = 6.5 Hz, 3H), 0.91 (s, 9H), 0.87 (s, 9H), 0.16 (s, 3H), 0.10 (s, 3H), 0 , 05 (s, 3H), 0.04 (s, 3H).
MS (ESI) m / z: 659.7 (M + 23).
R _f = 0.56 (Hex: EtOAc, 4: 1).

Example 83: Compounds 38a and 38b

To a solution of N-methoxy-N-methylacetamide (0.158 mL, 1.41 mmol) in dry THF (5 mL) was added at -78 ° C bis (trimethylsilyl) lithium amide (1.41 mL, 1.0 M in THF , 1.41 mmol) was added and the reaction mixture stirred for 1 h at this temperature. Subsequently, a solution of aldehyde 37 (0.47 mmol) in THF (10 mL) was added via the previous solution and the reaction mixture was stirred for a further 1 h at -78 ° C. Thereafter, a saturated aqueous solution of NH ₄ Cl (30 mL) was added and the reaction mixture extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hex: EtOAc, from 5: 1 to 1: 1) to give compounds 38a and 38b (38:62) as colorless oils (146 mg, in 42% overall yield). for 2 steps from 11a).
38a: ¹ H NMR (300 MHz, CDCl ₃₎ δ 7.25 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.81 to 5 , 86 (m, 1H), 5.07-5.22 (m, 2H), 4.46-4.50 (m, 1H), 4.44 (dd, J = 24.4 and 11.5 Hz , 2H), 4.05-4.16 (m, 1H), 3.65-3.94 (m, 3H), 3.79 (s, 3H), 3.53 (d, J = 4.7 Hz, 1H), 3.32-3.44 (m, 2H), 3.15-3.23 (m, 1H), 3.17 (s, 3H), 2.68-2.75 (m, 1H), 2.62 (d, J = 9.3Hz, 1H), 2.18-2.24 (m, 1H), 2.09-2.15 (m, 1H), 1.82-1 , 93 (m, 2H), 1.24 (s, 3H), 1.04 (d, J = 6.7 Hz, 3H), 0.91 (s, 9H), 0.86 (s, 9H) , 0.14 (s, 3H), 0.08 (s, 3H), 0.04 (s, 3H), 0.02 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 174.5, 159.3, 139.5, 136.4, 130.7, 129.3, 118.9, 114.0, 77.0, 73.0 , 72.7, 69.9, 68.4, 64.9, 64.2, 61.4, 61.3, 55.4, 55.0, 48.7, 36.5, 33.8, 32.1, 29.9, 26.3, 26, 0, 18.4, 18.1, 15.1, 14.1, -4.2, -5.0, -5.1, -5.2.
MS (ESI) m / z: 740.5 (M + 1) ⁺ , 762.6 (M + 23) ⁺ .
R _f = 0.08 (Hex: EtOAc, 4: 1).
38b: ¹ H NMR (300 MHz, CDCl _3): δ 7.23 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 5,95- 6.08 (m, 1H), 5.04-5.30 (m, 2H), 4.43 (dd, J = 11.8, 11.8Hz, 2H), 4.29-4.33 ( m, 1H), 4.12 (br s, 1H), 3.78-3.89 (m, 2H), 3.79 (s, 3H), 3.57-3.72 (m, 1H), 3.65 (s, 3H), 3.33-3.44 (m, 2H), 3.15 (s, 3H), 2.59 (d, J = 9.1Hz, 1H), 2.46 -2.62 (m, 1H), 1.73-1.89 (m, 2H), 1.24 (s, 3H), 1.06 (d, J = 6.7 Hz, 3H), 0, 91 (s, 9H), 0.86 (s, 9H), 0.15 (s, 3H), 0.08 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H ).
¹³ C NMR (75 MHz, CDCl ₃ δ 171.4, 159.3, 135.4, 130.6, 129.4, 119.2, 113.9, 77.6, 73.0, 72.8, 72.7, 70.3, 64.8, 64.3, 61.4, 60.8, 55.4, 52.8, 47.4, 36.7, 33.6, 29.9, 26, 3, 18.4, 18.2, 15.0, 14.0, 4.2, -5.0, -5.1, -5.2.
MS (ESI) m / z: 740.6 (M + 1) ⁺ , 762.6 (M + 23) ⁺ .
R _f = 0.10 (Hex: EtOAc, 4: 1).

Example 84: Compound 39a

To a solution of 38a (106 mg, 0.143 mmol) in CH ₂ Cl ₂ (8 mL) at 0 ° C was successively added 2,6-lutidine (0.051 mL, 0.44 mmol) and TBSOTf (0.05 mL, 0 , 22 mmol) was added. The reaction mixture was stirred at this temperature for 1 h. An aqueous solution of NaHCO ₃ (20 mL) was then added and extracted with CH ₂ Cl ₂ (2 x 20 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 10: 1) to give compound 39a (79 mg, 65%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.23 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 5.82 to 5.94 (m, 1H), 5.07-5.20 (m, 2H), 4.44 (dd, J = 18.8, 11.9Hz, 1H), 4.37-4.41 (m, 2H 3.91-3.95 (m, 1H), 3.80 (s, 3H), 3.67-3.79 (m, 2H), 3.64 (s, 3H), 3.30- 3.40 (m, 2H), 3.13 (s, 3H), 3.07 (d, J = 4.4Hz, 1H), 2.66-2.76 (m, 1H), 2.59 (d, J = 9.1Hz, 1H), 2.47 (dd, J = 15.6, 3.4Hz, 1H), 2.27-2.34 (m, 1H), 1.68 1.82 (m, 2H), 1.25 (s, 3H), 1.05 (d, J = 6.7Hz, 3H), 0.91 (s, 9H), 0.86 (s, 9H ), 0.85 (s, 9H), 0.14 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 172.5, 159.1, 135.8, 130.4, 129.0, 118.4, 113.8, 76.7, 72.9, 72.6 , 70.3, 69.0, 64.6, 61.4, 60.4, 56.0, 55.4, 47.3, 33.8, 29.9, 26.4, 26.1, 26 , 0, 18.5, 18.3, 18.1, 15.2, 14.0, -4.1, -4.2, -4.5, -5.0, -5.1.
MS (ESI) m / z: 854.4 (M + 1) ⁺ , 876.2 (M + 23) ⁺ .
R _f = 0.53 (Hex: EtOAc, 4: 1).

Example 85: Compound 39b

To a solution of 38b (89 mg, 0.12 mmol) in CH ₂ Cl ₂ (8 mL) at 0 ° C was successively added 2,6-lutidine (0.042 mL, 0.36 mmol) and TBSOTf (0.041 mL, 0 , 18 mmol) was added. The reaction mixture was stirred at this temperature for 1 h. A saturated aqueous solution of NaHCO ₃ (20 mL) was then added and the mixture extracted with CH ₂ Cl ₂ (2 x 20 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 10: 1) to give compound 39b (86 mg, 84%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.24 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 5.89 to 6.01 (m, 1H), 5.03-5.25 (m, 2H), 4.40 (dd, J = 18.4, 11.4Hz, 2H), 4.16-4.22 (m, 3H 3,79-3,86 (m, 1H), 3,79 (s, 3H), 3,63-3,70 (m, 1H), 3,67 (s, 3H), 3,27- 3.44 (m, 3H), 3.16 (s, 3H), 2.70-2.80 (m, 1H), 2.6 (d, J = 9.1Hz, 1H), 2.51 -2.58 (m, 1H), 2.27-2.32 (m 1H), 1.65-1.89 (m, 2H), 1.26 (s, 3H), 1.09 (d, J = 6.7 Hz, 3H), 0.92 (s, 9H), 0.87 (s, 9H), 0.86 (s, 9H), 0.13 (s, 3H), 0.10 ( s, 3H), 0.09 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 172.7, 159.4, 137.5, 130.5, 129.5, 118.5, 114.0, 76.4, 73.1, 72.7 , 69.1, 64.8, 64.1, 61.5, 61.0, 55.4, 54.4, 44.4, 37.3, 34.4, 32.1, 29.9, 26 , 6, 26,2, 26,0, 18,9, 18,2, 17,9, 15,4, 12,7, -4,0, -4,2, -4,7, -5,0 , -5,1.
MS (ESI) m / z: 854.4 (M + 1) ⁺ , 876.3 (M + 23) ⁺ .
R _f = 0.43 (Hex: EtOAc, 4: 1).

Example 86: Compound 40a

Ozone was passed through a solution of 39a (79 mg, 0.09 mmol) in CH ₂ Cl ₂ (15 mL) at -78 ° C until the clear solution turned to light blue (2 min). Then MeOH (15 mL) and NaBH ₄ (15 mg, 0.4 mmol) were added and the solution brought to 23 ° C over 2 h. The solvents are then removed under reduced pressure and the residue is dissolved in CH ₂ Cl ₂ , hydrolyzed with aqueous NH ₄ Cl and extracted with CH ₂ Cl ₂ (2 × 20 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hex: EtOAc, from 4: 1 to 2: 1) to give compound 40a (10 mg, 13%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.23 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.43 (dd, J = 19.6, 11.7 Hz, 2H), 4.20-4.33 (m, 2H), 3.61-4.07 (m, 5H), 3.81 (s, 3H), 3, 68 (s, 3H), 3.31-3.45 (m, 2H), 3.16 (s, 3H), 2.77-2.89 (m, 1H), 2.65 (d, J = 9.3Hz, 1H), 2.03-2.16 (m, 2H), 1.76-1.81 (m, 2H), 1.62-1.68 (m, 2H), 1.25 (s, 3H), 1.07 (d, J = 6Hz, 3H), 0.90 (s, 9H), 0.88 (s, 9H, 0.86 (s, 9H), 0.15 ( s, 3H), 0.12 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.08 (s, 3H), 0.00 (s, 3H).
MS (ESI) m / z: 880 (M + 23) ⁺ .
R _f = 0.15 (Hex: EtOAc, 4: 1).

Example 87: Compound 40b

Ozone was passed through a solution of 39b (86 mg, 0.1 mmol) in CH ₂ Cl ₂ (15 mL) at -78 ° C until the clear solution turned to light blue (2 min). Then MeOH (15 mL) and NaBH ₄ (15 mg, 0.4 mmol) were added and the solution brought to room temperature over 2 h. The solvents are then removed under reduced pressure and the residue is dissolved in CH ₂ Cl ₂ , hydrolyzed with aqueous NH ₄ Cl and extracted with CH ₂ Cl ₂ (2 × 20 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (hex: EtOAc, from 4: 1 to 2: 1) to give compound 40b (50 mg, 58%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃ ): δ 7.25 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 4.41 (dd, J = 19.3, 11.4Hz, 2H), 4.18-4.40 (m, 3H), 3.64-3.95 (m, 6H), 3.79 (s, 3H), 3 , 71 (s, 3H), 3.30-3.42 (m, 2H), 3.16 (s, 3H), 2.90-2.98 (m, 1H), 2.60 (d, J = 9.1Hz, 1H), 2.55-2.62 (m, 1H), 1.78-1.87 (m, 3H), 1.27 (s, 3H), 1.08 (d, J = 6.7 Hz, 3H), 0.92 (s, 9H), 0.86 (s, 9H), 0.85 (s, 9H), 0.14 (s, 3H), 0.12 ( s, 3H), 0.09 (s, 3H), 0.05 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 171.8, 159.2, 130.2, 129.4, 113.8, 75.8, 72.8, 72.5, 72.2, 68.7 , 64.5, 63.6, 63.2, 61.4, 60.7, 55.2, 48.5, 43.0, 37.4, 34.2, 31.9, 29.7, 26 , 3, 25.9, 25.7, 18.6, 17.9, 17.6, 15.2, 12.5, -4.4, -4.5, -5.1, .5, 2 , -5,4, -5,5.
MS (ESI) m / z: 880 (M + 23) ⁺ .
R _f = 0.13 (Hex: EtOAc, 4: 1).

Example 88: compound 41b

To a solution of 40b (50 mg, 0.06 mmol) in CH ₂ Cl ₂ (8 mL) at 0 ° C was successively 2,6-lutidine (0.021 mL, 0.18 mmol) and TBSOTf (0.021 mL, 0.09 mmol).

The reaction mixture was stirred at this temperature for 1 h. A saturated aqueous solution of NaHCO ₃ (20 mL) was then added and the mixture extracted with CH ₂ Cl ₂ (2 x 20 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 10: 1) to give compound 41b (57 mg, 98%) as a colorless oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 7.23 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 4.65 (m, 1H ), 4.41 (dd, J = 15.9, 11.7 Hz, 2H), 4.17-4.21 (m, 1H), 4.04-4.11 (m, 2H), 3, 79-3.86 (m, 1H), 3.80 (s, 3H), 3.66 (s, 3H), 3.25-3.31 (m, 1H), 3.16 (s, 3H) , 2.72-2.84 (m, 1H), 2.62 (d, J = 9.3Hz, 1H), 2.46-2.54 (m, 1H), 1.82-2.05 (m, 1H), 1.62-1.82 (m, 2H), 1.25 (s, 3H), 1.10 (d, J = 6.7Hz, 3H), 0.92 (s, 9H), 0.91 (s, 9H), 0.87 (s, 9H), 0.83 (s, 9H), 0.16 (s, 3H), 0.11 (s, 3H), 0, 10 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.05 (s, 3H), 0.03 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃₎ δ 173.1, 159.4, 130.0, 129.4, 114.0, 76.2, 72.8, 72.0, 69.2, 68.7 , 64.5, 63.7, 61.9, 61.5, 55.4, 51.2, 44.5, 34.4, 29.9, 26.5, 26.2, 26.1, 18 , 8, 18.4, 18.1, 17.9, 15.6, 12.3, -3.8, -4.6, -4.7, -5.0, -5.1, -5 ; 2.
MS (ESI) m / z: 972.6 (M + 1) ⁺ , 994.6 (M + 23) ⁺
R _f = 0.56 (Hex: EtOAc, 4: 1).

Example 89: compounds 43 and 44

43: ¹H NMR (300 MHz, CDCl₃) (Daten des Hauptproduktes) δ 5,53-5,45 (m, 1H), 5,31-5,19 (m, 1H), 4,45-4,40 (m, 2H), 3,92-3,80 (m, 3H), 3,53 (d, J = 9,9 Hz, 1H), 3,27-3,21 (m, 1H), 2,76-2,66 (m, 1H), 2,56 (d, J = 9,3 Hz, 1H), 2,49-2,41 (m, 1H), 2,06-2,00 (m, 1H), 2,03 (s, 3H), 1,68-1,66 (m, 3H), 1,62 (dd, J = 12,0, 6 Hz, 3H), 1,32 (s, 3H), 1,13 (d, J = 6,6 Hz, 3H), 0,97 (t, J = 7,5 Hz, 3H), 0,86 (s, 9H), 0,13 (s, 3H), –0,01 (s, 3H).
MS (ESI) m/z: 551 (M+23)⁺.
R_f = 0,39 (Hex:EtOAc, 50:50).

44: ¹H NMR (300 MHz, CDCl₃) δ 5,52-5,46 (m, 1H), 5,22-5,15 (m, 1H), 4,50 (dd, J = 11,0, 4,5 Hz, 1H), 4,47-4,43 (m, 1H), 4,34-4,33 (m, 1H) 4,13-4,07 (m, 1H), 3,90-3,81 (m, 1H), 3,70-3,65 (m, 1H), 3,56 (d, J = 9,3 Hz, 1H), 3,33-3,26 (m, 1H), 3,13-3,11 (m, 1H), 2,69-2,64 (m, 2H), 2,55 (d, J = 9,0 Hz, 1H), 2,48-2,39 (m, 2H), 2,09 (s, 3H), 2,00 (s, 3H), 1,67-1,61 (m, 3H), 1,32 (s, 3H), 1,13 (d, J = 6,3 Hz, 3H), 1,05 (t, J = 7 Hz, 3H), 0,85 (s, 9H), 0,15 (s, 3H), –0,01 (s, 3H).
MS (ESI) m/z: 593 (M+23)⁺.
R_f = 0,53 (Hex:EtOAc, 50:50).To a solution of 20b (14 mg, 0.024 mmol) in CHCl ₃ (3 mL) was added Et ₃ N (28 μL, 0.2 mmol) and Ac ₂ O (10 μL, 0.1 mmol) at 23 ° C , The reaction mixture was stirred at 23 ° C for 16 h. The solvent was then removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (hex: EtOAc, from 2: 1 to 1: 1), then the pure compounds 43 (6 mg, 47%) and 44 (6 mg , 44%) as a white solid.

43: ¹ H NMR (300 MHz, _CDCl3) (data of the major product) δ 5.53 to 5.45 (m, 1H), 5.31 to 5.19 (m, 1H), 4.45 to 4, 40 (m, 2H), 3.92-3.80 (m, 3H), 3.53 (d, J = 9.9 Hz, 1H), 3.27-3.21 (m, 1H), 2 , 76-2.66 (m, 1H), 2.56 (d, J = 9.3Hz, 1H), 2.49-2.41 (m, 1H), 2.06-2.00 (m , 1H), 2.03 (s, 3H), 1.68-1.66 (m, 3H), 1.62 (dd, J = 12.0, 6 Hz, 3H), 1.32 (s, 3H), 1.13 (d, J = 6.6Hz, 3H), 0.97 (t, J = 7.5Hz, 3H), 0.86 (s, 9H), 0.13 (s, 3H), -0.01 (s, 3H).
MS (ESI) m / z: 551 (M + 23) ⁺ .
R _f = 0.39 (Hex: EtOAc, 50:50).

44: ¹ H NMR (300 MHz, CDCl ₃₎ δ 5.52 to 5.46 (m, 1H), 5.22 to 5.15 (m, 1H), 4.50 (dd, J = 11.0 , 4.5Hz, 1H), 4.47-4.43 (m, 1H), 4.34-4.33 (m, 1H) 4.13-4.07 (m, 1H), 3.90 -3.81 (m, 1H), 3.70-3.65 (m, 1H), 3.56 (d, J = 9.3Hz, 1H), 3.33-3.26 (m, 1H 3.13-3.11 (m, 1H), 2.69-2.64 (m, 2H), 2.55 (d, J = 9.0 Hz, 1H), 2.48-2, 39 (m, 2H), 2.09 (s, 3H), 2.00 (s, 3H), 1.67-1.61 (m, 3H), 1.32 (s, 3H), 1.13 (d, J = 6.3Hz, 3H), 1.05 (t, J = 7Hz, 3H), 0.85 (s, 9H), 0.15 (s, 3H), -0.01 ( s, 3H).
MS (ESI) m / z: 593 (M + 23) ⁺ .
R _f = 0.53 (Hex: EtOAc, 50:50).

Example 90: compound 45

To a solution of 20b (34 mg, 0.07 mmol) in CH ₂ Cl ₂ (0.7 mL) was added Et ₃ N (11.5 μL, 0.82 mmol), DMAP (5 mg, 0.041 mmol) and Ac ₂ O (39 μL, 0.4 mmol) at 0 ° C. The reaction mixture was stirred at 23 ° C for 3 h. Then, 0.1N HCl was added until pH = 4-5, and the reaction mixture was extracted with CH ₂ Cl ₂ (2 x 5 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, 3: 1) to give compound 45 (17 mg, 40%) as a yellow oil.
¹ H NMR (300 MHz, CDCl ₃₎ δ 5.60 to 5.56 (m, 1H), 5.54 to 5.44 (m, 1H), 5.26 to 5.19 (m, 1H), 4.46 (dd, J = 11.1, 5.7 Hz, 1H), 4.35 (dd, J = 11.4, 3.3 Hz, 1H), 4.14 (dd, J = 12, 0, 6.9 Hz, 1H), 3.87 (dd, J = 11.4, 8.1 Hz, 1H), 3.55-3.49 (m, 2H), 3.46-3.38 (m, 2H), 2.79-2.76 (m, 2H), 2.52 (d, J = 9.3Hz, 1H), 2.45-2.38 (m, 3H), 2, 06 (s, 3H), 1.99 (s, 6H), 1.62 (dd, J = 6.9, 1.8 Hz, 1H), 1.33 (s, 3H), 1.11 (i.e. , J = 6.3 Hz, 3H), 1.03 (t, J = 7.2 Hz, 3H), 0.85 (s, 9H), 0.13 (s, 3H), 0.00 (s , 3H).
MS (ESI) m / z: 635 (M + 23) ⁺ .
R _f = 0.54 (Hex: EtOAc, 50:50).

Example 91: compound 46

To a solution of 20a (18 mg, 0.037 mmol) in CH ₂ Cl ₂ (3 mL) was added Et ₃ N (21 μL, 0.15 mmol) and Ac ₂ O (7 μL, 0.074 mmol) at 23 ° C , The reaction mixture was stirred at 23 ° C for 16 h. Then NaHCO ₃ (5 mL) was added and the reaction extracted with CH ₂ Cl ₂ (2 × 5 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (Hex: EtOAc, from 3: 1 to 2: 1) to give Compound 46 (16 mg, 82%) as a white solid.
¹ H NMR (300 MHz, CDCl ₃ ) (main product data) δ 5.55-5.45 (m, 1H), 5.26-5.19 (m, 1H), 5.06 (s, 1H) , 4.56 (bs, 1H), 4.45 (dd, J = 11.4, 3.6Hz, 1H), 4.22 (t, J = 117Hz, 1H), 4.06 (bs, 1H), 3.97-3.82 (m, 2H), 3.47 (d, J = 9.6Hz, 1H), 3.21-3.14 (m, 1H), 2.94-2 , 89 (m, 1H), 2.56 (d, J = 9.0 Hz, 1H), 2.06-2.98 (m, 1H), 2.02 (s, 3H), 1.63 1.58 (m, 6H), 1.30 (s, 3H), 1.13 (d, J = 6.6 Hz, 3H), 0.94 (t, J = 7.5 Hz, 3H), 0.85 (s, 9H), 0.13 (s, 3H), -0.01 (s, 3H).
¹³ C NMR (75 MHz, CDCl ₃ ) (main product data) δ 212.2, 170.4, 130.5, 125.3, 97.5, 77.5, 66.0, 65.6, 62, 2, 62.1, 55.9, 54.2, 54.1, 37.4, 34.6, 31.6, 29.9, 26.2, 20.9, 18.9, 13.5, 11.8, 7.7, -4.2, -4.6.
MS (ESI) m / z: 551 (M + 23) ⁺ .
R _f = 0.38 (Hex: EtOAc, 2: 1).

Example 92: Compounds 47 and 1

47: ¹H NMR (500 MHz CD₃OD) (Daten des Hemiketalproduktes) δ 5,50 (m, 1H), 5,26 (m, 1H), 4,57 (m, 1H), 4,28 (dd, J = 12,5, 12,0 Hz, 1H), 4,15 (dd, J = 110, 4,0 Hz, 1H), 4,00 (dd, J = 1 1,0, 9,5 Hz, 1H), 3,69 (dd, J = 12,5, 5,0 Hz, 1H), 3,40 (m, 1H), 3,13 (d, J = 10,5 Hz, 1H), 2,97 (ddd, J = 12,0, 5,0, 2,5 Hz, 1H), 2,62 (d, J = 9,5 Hz, 1H), 2,47 (m, 1H), 1,97 (s, 3H), 1,93 (dd, J = 14,0, 3,0 Hz, 1H), 1,72 (dd, J = 14,0, 3,0 Hz, 1H), 1,64 (brd, J = 7,0 Hz, 3H), 1,57 (d, J = 7,5 Hz, 2H), 1,37 (s, 3H), 1,09 (d, J = 7,0 Hz, 3H), 0,92 (t, J = 7,5 Hz, 3H).
¹³C NMR (125 MHz CD₃OD) (Daten des Hemiketalproduktes) δ 212,6, 172,6, 131,5, 126,1, 98,8, 78,6, 67,6, 66,1, 64,3, 62,9, 56,8, 56,0, 52,2, 38,6, 35,6, 32,3, 20,8, 18,8, 13,6, 11,6, 7,9.
MS (ESI) m/z: 437 (M+23)⁺.

1: ¹H NMR (500 MHz MeOD) δ 6,27 (s, 1H), 6,22 (d, J = 1,2 Hz, 1H), 5,55-5,46 (m, 1H), 5,30-5,23 (m, 1H), 5,04-5,01 (m, 1H), 4,32 (dd, J = 10,5, 3,9 Hz, 1H), 3,88 (dd, J = 9,9, 9,9 Hz, 1H), 3,76 (ddd, J = 19,8, 9,9, 3,6 Hz 1H), 3,34 (d, J = 9,9 Hz), 1,94 (s, 3H), 1,65 (dd, J = 6,9, 1,8 Hz, 1H), 1,38 (d, J = 6,6 Hz, 3H), 1,01 (t, J = 7,5 Hz, 3H).
MS (ESI) m/z: 419 (M+23)⁺.
R_f = 0,37 (Hex:EtOAc, 1:2).To a solution of crude product 4a (20 mg, 0.054 mmol) in CHCl ₃ (3 mL) was added Et ₃ N (22 μL, 0.16 mmol) and Ac ₂ O (8 μL, 0.081 mmol) at 23 ° C. The reaction mixture was stirred at 23 ° C for 16 h. The solvent was then removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (hex: EtOAc, from 2: 1 to 1: 1) to give pure compounds 47 (10 mg, 48%) and 1 (4 mg , 44%) as yellow oils.

47: ¹ H NMR (500 MHz CD ₃ OD) (data of the Hemiketalproduktes) δ 5.50 (m, 1H), 5.26 (m, 1H), 4.57 (m, 1H), 4.28 (dd , J = 12.5, 12.0 Hz, 1H), 4.15 (dd, J = 110, 4.0 Hz, 1H), 4.00 (dd, J = 1.0, 9.5 Hz , 1H), 3.69 (dd, J = 12.5, 5.0 Hz, 1H), 3.40 (m, 1H), 3.13 (d, J = 10.5 Hz, 1H), 2 , 97 (ddd, J = 12.0, 5.0, 2.5 Hz, 1H), 2.62 (d, J = 9.5 Hz, 1H), 2.47 (m, 1H), 1, 97 (s, 3H), 1.93 (dd, J = 14.0, 3.0 Hz, 1H), 1.72 (dd, J = 14.0, 3.0 Hz, 1H), 1.64 (brd, J = 7.0 Hz, 3H), 1.57 (d, J = 7.5 Hz, 2H), 1.37 (s, 3H), 1.09 (d, J = 7.0 Hz , 3H), 0.92 (t, J = 7.5 Hz, 3H).
¹³ C NMR (125 MHz CD ₃ OD) (Hemiketal Product Data) δ 212.6, 172.6, 131.5, 126.1, 98.8, 78.6, 67.6, 66.1, 64, 3, 62.9, 56.8, 56.0, 52.2, 38.6, 35.6, 32.3, 20.8, 18.8, 13.6, 11.6, 7.9.
MS (ESI) m / z: 437 (M + 23) ⁺ .

1: ¹ H NMR (500 MHz MeOH) δ 6.27 (s, 1H), 6.22 (d, J = 1.2 Hz, 1H), 5.55-5.46 (m, 1H), 5 , 30-5.23 (m, 1H), 5.04-5.01 (m, 1H), 4.32 (dd, J = 10.5, 3.9Hz, 1H), 3.88 (d , J = 9.9, 9.9 Hz, 1H), 3.76 (ddd, J = 19.8, 9.9, 3.6 Hz 1H), 3.34 (d, J = 9.9 Hz ), 1.94 (s, 3H), 1.65 (dd, J = 6.9, 1.8 Hz, 1H), 1.38 (d, J = 6.6 Hz, 3H), 1.01 (t, J = 7.5 Hz, 3H).
MS (ESI) m / z: 419 (M + 23) ⁺ .
R _f = 0.37 (Hex: EtOAc, 1: 2).

Example 93: BIOASSAYS FOR ANTITUMOR SCREENING

The ultimate goal of these assays is to stop the growth of an "in vitro" tumor cell culture by continuously exposing the cells to the test substance. CELL LINES SURNAME N ° ATCC SPECIES TISSUE PROPERTIES K-562C CCL-243 human leukemia Erythroleukemia (pleural effusion) A-549 C CCL-185 human lung Lung Carcinoma "NSCL" SK-MEL-28 HTB-72 human melanoma malignant melanoma HT-29 HTB-38 human colon Adenocarcinoma of the colon L _o V _o CCL-229 human colon Adenocarcinoma of the colon LoVo Dox human colon Adenocarcinoma of the large intestine (MDR) DU-145 HTB-81 human prostate Prostate cancer, no androgen receptors LNCaP CRL-1740 human prostate Prostate adenocarcinoma, with androgen receptors SK-BR-3 HTB-30 human chest Breast adenocarcinoma, Her2 / neu +, (pleural effusion) IGROV human ovary Ovarian adenocarcinoma IGROV-ET human ovary Ovarian adenocarcinoma, characterized as ET-743 resistant cells HeLa CCL-2 human cervix Cervix epitheloid carcinoma HeLa APL CCL-3 human cervix Cervix, epitheloid carcinoma, characterized as aplidine-resistant cells PANC-1 CRL-1469 human pancreas Epitheloid pancreatic carcinoma

INHIBITION OF CELL GROWTH BY COLORIMETRIC ASSAY.

One colorimetric assay using the sulforhodamine B (SRB) reaction for a quantitative Determination of cell growth and viability used was adjusted (corresponding to P. A. Skehan, et al., J. Natl. Cancer Inst. 1990, 82, 1107-1112).

These Assay mold uses 96-well cell culture microplates of 9 mm diameter (T.Mosmann et al., J. of Immunological Methods 1983, 65, 55-63; G.T. Faircloth et al., J. of Tissue and Culture Methods 1988, 11, 201-205). Most of the cell lines were from the "American Type Culture Collection (ATCC) ", and came from different human cancers.

Cells are stored in RPMI 1640 10% FBS, to which are added 0.1 g / L penicillin and 0.1 g / L streptomycin sulfate and then incubated at 37 ° C, 5% CO ₂ and 98% humidity. For the experiments, the cells were taken from subconfluent cultures with trypsin and prior to the application of a plat crops are resuspended in fresh medium.

Cells were seeded in 96-well microtiter plates, at 5 x 10 ³ cells per well in aliquots to 195 μL medium, and then cultured in drug-free medium for 18 hours to bind to the plate surfaces. Thereafter, the samples dissolved in DMSO / EtOH / PBS (0.5: 0.5: 99) were added in aliquots of 5 μL in the concentration range of 10 to 10 ^-8 mg / mL. After 48 hours of exposure, antitumor activity was measured by the SRB method. Cells were fixed by addition of 50 μL of cold 50% (wt / vol) trichloroacetic acid (TCA) and incubated for 60 minutes at 4 ° C. The plates were washed with deionized water and dried. One hundred μL of the SRB solution (0.4% wt / vol in 1% acetic acid) was added to each well of the microtiter plate and incubated for 10 minutes at room temperature. Unbound SRB was removed by washing with 1% acetic acid. The plates were air dried and adherent spots were dissolved with Tris buffer. The optical density values were measured with an automated spectrophotometric plate reader at a single wavelength of 490 nm.

The Values for average +/- SD Data were triplicated calculated in the wells. Some parameters of the cell responses can be calculated GI = growth inhibition, TGI = total Growth inhibition (cytostatic effect) and LC = cell killing (cytotoxic effect).

Table 1 shows data on the biological activity of the compounds of the present invention. TABLE 1: ACTIVITY DATA (MOLAR) 19a 19b 20a + 20c 20b + 20d 31b + 31d DU-145 GI50 TGI LC50 1,21E-05 1,21E-05 1,21E-05 1,20E-05 1,20E-05 1,20E-05 1,07E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 LN-caP GI50 TGI LC50 1,21E-05 1,21E-05 1,21E-05 1,20E-05 1,20E-05 1,20E-05 8,42E-06 2,05E-05 2,05E-05 1,24E-05 2,05E-05 2,05E-05 - - - IGROV GI50 TGI LC50 1,21E-05 1,21E-05 1,21E-05 1,20E-05 1,20E-05 1,20E-05 1,41E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 1,65E-05 2,05E-05 2,05E-05 IGROV-ET GI50 TGI LC50 1,21E-05 1,21E-05 1,21E-05 1,20E-05 1,20E-05 1,20E-05 1,38E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 SK-BR-3 GI50 TGI LC50 1,21E-05 1,21E-05 1,21E-05 6,15E-06 1,17E-05 1,20E-05 1,11E-05 2,05E-05 2,05E-05 1,49E-05 2,05E-05 2,05E-05 2,02E-05 2,05E-05 2,05E-05 MEL-28 GI50 TGI LC50 1,21E-05 1,21E-05 1,21E-05 1,20E-05 1,20E-05 1,20E-05 1,63E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 A-549 GI50 TGI LC50 1,21E-05 1,21E-05 1,21E-05 1,20E-05 1,20E-05 1,20E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 K-562 GI50 TGI LC50 1,21E-05 1,21E-05 1,21E-05 1,20E-05 1,20E-05 1,20E-05 7,75E-06 2,05E-05 2,05E-05 1,03E-05 2,05E-05 2,05E-05 - - - PANC-1 GI50 TGI LC50 1,21E-05 1,21E-05 1,21E-05 1,20E-05 1,20E-05 1,20E-05 1,40E-05 2,05E-05 2,05E-05 9,37E-06 2,05E-05 2,05E-05 1,26E-05 2,05E-05 2,05E-05 HT-29 GI50 TGI LC50 1,21E-05 1,21E-05 1,21E-05 1,20E-05 1,20E-05 1,20E-05 1.71E-05 2.05E-05 2.05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 LOVO GI50 TGI LC50 1,21E-05 1,2IE-05 1,2IE-05 1,20E-05 1,20E-05 1,20E-05 1,04E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 LOVO DOX GI50 TGI LC50 1,21E-05 1,21E-05 1,21E-05 1,20E-05 1,20E-05 1,20E-05 8,51E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 HELA GI50 TGI LC50 1,21E-05 1,21E-05 1,21E-05 1,20E-05 1,20E-05 1,20E-05 1,33E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 HeLa APL GI50 TGI LC50 1,21E-05 1,21E-05 1,21E-05 1,20E-05 1,20E-05 1,20E-05 1,29E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 2,05E-05 TABLE 1 (CONTINUED): ACTIVITY DATA (MOLAR) 30a 30b 3a + 4a 3b + 4b 3c + 4c 3d + 4d DU-145 GI50 TGI LC50 1,21E-05 1,21E-05 1,21E-05 1,21E-05 1,21E-05 1,21E-05 6,31E-08 4,03E-07 2,03E-06 6,52E-06 2,68E-05 2,68E-05 5,50E-07 4,16E-06 2,68E-05 2,68E-05 2,68E-05 2,68E-05 LN-caP GI50 TGI LC50 - - - - - - 8,19E-08 5,53E-07 5,32E-06 9.29E-06 2.68E-05 2.68E-05 7,03E-07 4,56E-06 2,65E-05 - - - IGROV GI50 TGI LC50 - - - - - - 7,30E-08 3,76E-07 3,92E-06 5,96E-06 2,68E-05 2,68E-05 5,53E-07 3,57E-06 2,09E-05 2,05E-05 2,68E-05 2,68E-05 IGROV-ET GI50 TGI LC50 8,27E-06 1,21E-05 1,21E-05 8,27E-06 1,21E-05 1,21E-05 1,00E-07 1,07E-06 2,68E-05 6,55E-06 2,68E-05 2,68E-05 7,03E-07 6,95E-06 2,68E-05 1.71E-05 2.68E-05 2.68E-05 SK-BR-3 GI50 TGI LC50 8,56E-06 1,21E-05 1,21E-05 1,21E-05 1,21E-05 1,21E-05 3.03E-08 4,75E-07 5,34E-06 5,07E-06 1,09F-05 2,33E-05 1,16E-06 6,07E-06 2,68E-05 2,05E-05 2,68E-05 2,68E-05 MEL-28 GI50 TGI LC50 1,21E-05 1,21E-05 1,21E-05 1,21E-05 1,21E-05 1,21E-05 7.54E-08 8.32E-07 1.20E-05 5,53E-06 2,68E-05 2,68E-05 6,34E-07 7,25E-06 2,68E-05 2,68E-05 2,68E-05 2,68E-05 A-549 GI50 TGI LC50 1,21E-05 1,21E-05 1,21E-05 1,21E-05 1,21E-05 1,21E-05 1.44E-07 2.59E-06 1.56E-05 2,68E-05 2,68E-05 2,68E-05 9,13E-07 1,34E-05 2,68E-05 2,68E-05 2,68E-05 2,68E-05 K-562 GI50 TGI LC50 - - - - - - 5,21E-07 1,46E-06 8,40E-06 1.42E-05 1.82E-05 2.33E-05 4,59E-06 1,19E-05 2,68E-05 - - - PANC-1 GI50 TGI LC50 1,21E-05 1,21E-05 1,21E-05 1,21E-05 1,21E-05 1,21E-05 8,97E-08 2,95E-06 2,68E-05 2,68E-05 2,68E-05 2,68E-05 1.03E-06 1.33E-05 2.68E-05 1,35E-05 2,68E-05 2,68E-05 HT-29 GI50 TGI LC50 - - - - - - 6.01E-08 1.18E-06 2.68E-05 2,21E-05 2,68E-05 2,68E-05 5,64E-07 6,69E-06 2,68E-05 2,68E-05 2,68E-05 2,68E-05 LOVO GI50 TGI LC50 6,37E-06 1,21E-05 1,21E-05 6,88E-06 1,21E-05 1,21E-05 8,22E-08 1,35E-06 1,77E-05 4,81E-06 1,26E-05 2,68E-05 7,14E-07 7,01E-06 2,68E-05 2,68E-05 2,68E-05 2,68E-05 LOVO DOX GI50 TGI LC50 1,21E-05 1,21E-05 1,21E-05 1,21E-05 1,21E-05 1,21E-05 1,52E-07 1,36E-06 2,68E-05 9.34E-06 2.68E-05 2.68E-05 8,46E-07 6,18E-06 2,68E-05 2,68E-05 2,68E-05 2,68E-05 HELA GI50 TGI LC50 1,21E-05 1,21E-05 1,21E-05 1,21E-05 1,21E-05 1,21E-05 7,28E-08 5,50E-07 7,14E-06 8.73E-06 2.68E-05 2.68E-05 6,20E-07 4,78E-06 2,68E-05 2,68E-05 2,68E-05 2,68E-05 HeLa APL GI50 TGI LC50 1,21E-05 1,21E-05 1,21E-05 1,21E-05 1,21E-05 1,21E-05 7.33E-08 9.83E-07 1.47E-05 5,18E-06 2,68E-05 2,68E-05 5.93E-07 8.67E-06 2.68E-05 2,68E-05 2,68E-05 2,68E-05 TABLE 1 (CONTINUED): ACTIVITY DATA (MOLAR) 46 43 44 45 47 1 DU-145 GI50 TGI LC50 9,65E-06 1,89E-05 1,89E-05 4.99E-06 9.66E-06 1.87E-05 4,99E-06 1,04E-05 1,75E-05 1.63E-05 1.63E-05 1.63E-05 8,15E-08 5,31E-07 2,41E-05 3,66E-06 1,02E-05 2,52E-05 LN-caP GI50 TGI LC50 5,24E-06 9,06E-06 1,56E-05 3,78E-06 7,62E-06 1,54E-05 3,77E-06 7,88E-06 1,66E-05 8.34E-06 1.63E-05 1.63E-05 8,13E-08 5,36E-07 8,88E-06 1,45E-06 6,31E-06 2,52E-05 IGRROV GI50 TGI LC50 7.74E-06 1.89E-05 1.89E-05 4,94E-06 9,99E-06 1,89E-05 4,13E-06 7,67E-06 1,42E-05 1.63E-05 1.63E-05 1.63E-05 6,39E-08 5,28E-07 2,41E-05 1.63E-06 5.67E-06 1.76E-05 IGROV-ET GI50 TGI LC50 7,39E-06 1,89E-05 1,89E-05 4,52E-06 8,96E-06 1,78E-05 4,15E-06 8,09E-06 1,58E-05 1,58E-05 1,63E-05 1,63E-05 1,52E-07 1,08E-06 2,41E-05 3,10E-06 8,58E-06 2,37E-05 SK-BR-3 GI50 TGI LC50 - - - - - - - - - - - - 2,31E-08 1,18E-07 2,30E-06 4,69E-07 1,11E-05 3,43E-06 MEL-28 GI50 TGI LC50 9.89E-06 1.89E-05 1.89E-05 3,90E-06 7,24E-06 1,34E-05 3,84E-06 6,96E-06 1,26E-05 1.63E-05 1.63E-05 1.63E-05 8,20E-08 9,84E-07 1,29E-05 2,72E-06 6,10E-06 1,36E-05 A-549 GI50 TGI LC50 1.34E-05 1.89E-05 1.89E-05 4,44E-06 8,49E-06 1,62E-05 4.01E-06 7.87E-06 1.54E-05 1.63E-05 1.63E-05 1.63E-05 1,51E-07 1,12E-06 2,32E-05 1,10E-06 5,04E-06 2,35E-05 K-562 GI50 TGI LC50 1.20E-05 1.89E-05 1.89E-05 3,59E-06 7,72E-06 1,65E-05 6,10E-06 1,14E-05 1,75E-05 1.63E-05 1.63E-05 1.63E-05 2,94E-07 9,99E-07 1,18E-05 1,99E-06 7,36E-06 2,46E-05 PANC-1 GI50 TGI LC50 7,38E-06 1,89E-05 1,89E-05 3,73E-06 7,02E-06 1,32E-05 3,73E-06 7,20E-06 1,38E-05 8,24E-06 1,63E-05 1,63E-05 9,05E-08 2,38E-06 1,95E-05 3,33E-06 8,40E-06 2,13E-05 HT-29 GI50 TGI LC50 1,50E-05 1,89E-05 1,89E-05 4,24E-06 8,28E-06 1,62E-05 6,22E-06 1,75E-05 1,70E-05 1.63E-05 1.63E-05 1.63E-05 1.06E-07 3,11E-06 2,41E-05 1.67E-06 5.37E-06 1.34E-05 LOVO GI50 TGI LC50 4,37E-06 1,00E-05 1,89E-05 4.03E-06 9.06E-06 1.89E-05 4.05E-06 8,99E-06 1,75E-05 8,26E-06 1,63E-05 1,63E-05 4.03E-08 3.74E-07 1.77E-05 1.62E-06 4.37E-06 1.26E-05 LOVO DOX GI50 TGI LC50 6,15E-06 1,89E-05 1,89E-05 3,31E-06 7,21E-06 1,57E-05 4,27E-06 8,90E-06 1,75E-05 1,05E-05 1,63E-05 1,63E-05 2,16E-07 2,41E-05 2,41E-05 3,13E-06 8,10E-06 2,11E-05 HELA GI50 TGI LC50 8,81E-06 1,89E-05 1,89E-05 4,37E-06 8,47E-06 1,64E-05 3,91E-06 7,59E-06 1,47E-05 1.63E-05 1.63E-05 1.63E-05 7,17E-08 4,34E-07 1,35E-05 1,99E-06 6,66E-06 2,05E-05 LA-APL GI50 TGI LC50 1.01E-05 1.89E-05 1.89E-05 4,27E-06 9,34E-06 1,89E-05 3,77E-06 9,83E-06 1,75E-05 1.63E-05 1.63E-05 1.63E-05 7,96E-08 5,91E-07 2,41E-05 1,72E-06 6,23E-06 2,20E-03

Claims (49)

Compound of the general formula I or a pharmaceutically acceptable salt, derivative or

wherein the substituent groups defined by R are each independently selected from the group consisting of H, SiR ' ₃ , SOR', SO ₂ R ', C (= O) R', C (= O) OR ', C (= O ) NR ', substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, heteroaryl or aralkyl; the group R 'is selected from substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aminoalkyl, aryl, aralkyl and a heterocyclic group; and the group R "is selected from the group consisting of H, OH, OR ', OCOR', SH, SR ', SOR', SO ₂ R ', NO ₂ , NH ₂ , NHR', N (R ') ₂ , NHCOR ', N (COR') ₂ , NHSO ₂ R ', CN, halogen, C (O) H, C (= O) R', CO ₂ H, CO ₂ R ', CH ₂ OR, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkylidene, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, and substituted or unsubstituted heteroaromatic; the substituents are selected from halogen, cyano, hydroxyl, nitro, azido, carboxamido; Alkyl, alkenyl, alkynyl, alkoxy, aryloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, aminoalkyl, aryl and a heterocyclic compound; with the proviso that the compound is not the natural compound designated MT332 or MT381. A compound according to claim 1, having the following stereochemistry

A compound according to claim 1, wherein R "is CH ₂ OH

which may be present as an isomeric mixture of the ketone and the hemiketal, or in one of the two isomeric forms. A compound according to claim 3, having the following stereochemistry

A compound according to claim 4, having the following stereochemistry

A compound according to claim 4, having the following stereochemistry

A compound according to claim 1 or 2 wherein R "is a substituted or unsubstituted one Alkylidene is. A compound according to any one of claims 3 to 6, wherein at least one of the R substituents C (= O) R 'is. A compound according to claim 8, having the formula 47

A compound according to claim 1, wherein at least one the substituent R is not hydrogen. A compound according to claim 10, wherein each group R, which is not hydrogen, is a protecting group that is the same or can be different. A compound according to claim 11, having the formula

wherein R ¹ , R ² , R ⁶ and R ^{7 are} protective groups for hydroxy. A compound according to claim 12, having the formula 19

wherein R ¹ , R ² , R ⁶ and R ^{7 are} protective groups for hydroxy A compound according to claim 12, having the formula 30

wherein R ¹ , R ² , R ⁶ and R ^{7 are} protective groups for hydroxy. A compound according to any one of claims 12-14, wherein R ¹ , R ² , R ⁶ and R ^{7 are} the same protecting group. A compound according to any one of claims 12-15, wherein R ¹ , R ² , R ⁶ and R ^{7 are} selected from TBS (tBuMe ₂ Si), TBDPS (tBuPh ₂ Si), TES (Et ₃ Si), MOM ( CH ₃ OCH ₂ -), MEM (CH ₃ OCH ₂ CH ₂ OCH ₂ -), SEM ((CH ₃ ) ₃ SiCH ₂ CH ₂ OCH ₂ -) and Ac- (CH ₃ CO-). A compound according to claim 16, wherein R ¹ , R ² , R ⁶ and R ^{7 are} selected from TBS (tBuMe ₂ Si) and TBDPS (tBuPh ₂ Si). A compound according to claim 11, having the formula

wherein R ^{1 is} a protecting group for hydroxy. A compound according to claim 18, having the formula 20:

A compound according to claim 11, having the formula 31:

A compound according to any one of claims 11 to 20, wherein R ^{1 is} TBS (tBuMe ₂ Si). A pharmaceutical composition comprising a Compound of the formula I or a pharmaceutically acceptable salt, Derivative, stereoisomer, or an intermediate in their synthesis, as in any of the claims 1 to 21, and a pharmaceutically acceptable carrier. The use of a compound of formula I or a pharmaceutically acceptable salt, derivative or stereoisomer thereof as defined in any one of claims 1 to 21, for Preparation of a medicament for the treatment of a tumor. Process for the synthesis of a myriaporone compound of formula 5

which may be present as an isomeric mixture of the ketone and the hemiketal, or in one of the two isomeric forms; wherein the substituent groups defined by R are as defined in claim 1; the removal of a protecting group from an intermediate of the formula

in which the substituent groups defined by R are each independently selected from the group consisting of H, SiR ' ₃ , SOR', SO ₂ R ', C (= O) R', C (= O) OR ', C ( = O) NR ', substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, heteroaryl or aralkyl, and wherein R or any group R converted to hydrogen in compound 5 in the intermediate is a protecting group ; and wherein the group R 'is as defined. The method of claim 24, wherein more than one Group R in the intermediate is a protecting group. The method of claim 24, which comprises removing at least one protecting group from a compound of formula 19

wherein R ¹ , R ² , R ⁶ and R ⁷ are hydroxy protecting groups. The method of claim 24, which comprises removing at least one protecting group from a compound of formula 30

wherein R ¹ , R ² , R ⁶ and R ⁷ are hydroxy protecting groups. A process according to any one of claims 24 to 27, wherein R ¹ , R ² , R ⁶ and R ^{7 are the} same protecting groups and are removed. The method of claim 24, which comprises removing a protecting group from a compound of formula 20

wherein R ^{1 is} a protecting group for hydroxy. The method of claim 24, which comprises removing a protecting group from a compound of formula 31

wherein R ^{1 is} a protecting group for hydroxy. Process for the synthesis of a myriaporone compound of formula I

wherein the substituent groups defined as R and R "are as defined in claim 1; which is the derivatization of a compound of formula 5

which may be present as a mixture of isomers of the ketone and the hemiketal, or in one of the two isomeric forms. and wherein the substituent groups are as defined in claim 1. Process according to any one of claims 24 to 31, when carried out according to the steps in Scheme 1 beginning with compound 6.

Scheme 1 wherein R ¹ , R ² , R ⁶ and R ⁷ are hydroxy protecting groups. Process according to any one of claims 24 to 31, when carried out according to the steps in Scheme 2 starting with compound 6

Scheme 2 wherein R ¹ , R ² , R ⁶ and R ⁷ are hydroxy protecting groups. Compound of the formula

wherein R ¹ , R ² and R ^{4 are} protective groups for hydroxy, and L is a stereospecific leaving group which generates chirality. A compound according to claim 34, having the formula 10:

A compound according to claim 34, having the formula 22:

Compound of the formula

wherein R ¹ , R ² , R ⁴ and R ⁶ are hydroxy protecting groups R ^{5 is} selected from the group consisting of H, SOR ', SO ₂ R', N (Me) (MeO), substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, aryl, heteroaryl or aralkyl; and R 'has the same meaning as defined in claim 1. A compound according to claim 37, wherein R ^{5 is} N (Me) (MeO). A compound according to claim 37, having the formula 14:

A compound according to claim 37, having the formula 26:

Process for the preparation of a compound of the formula 14, which is the chain extension a compound of formula 13. Process for the preparation of a compound of the formula 26, which is the chain extension a compound of formula 25. Process for the preparation of a compound of the formula 19, which is the chain extension a compound of formula 18. Process for the preparation of a compound of the formula 30, which is the chain extension a compound of formula 29. Compound of the formula

wherein R ¹ , R ² and R ^{4 are} protective groups for hydroxy. A compound according to claim 45, having the formula 11:

A compound according to claim 45, having the formula 23:

Compound of the formula

wherein R ¹ , R ² and R ^{4 are} protective groups for hydroxy. A compound according to claim 48, having the formula 8: